exv10w16



 







Exhibit 10.16







Confidential
Materials omitted and filed separately with the

Securities and Exchange Commission. Asterisks denote omissions.






DATED 18th Day of March 2005




(1) THE WELLCOME TRUST




AND




(2) MICROSCIENCE HOLDINGS PLC




AND




(3) MICROSCIENCE LIMITED



 




INVESTMENT AGREEMENT




RELATING TO




MICROSCIENCE HOLDINGS PLC



 




Ref: NKM/SJM/WELTR.0011





 









 








CONTENTS




	 	 	 	 	 
	1. INTERPRETATION
	 	 	1	 
	2. COMPLETION
	 	 	8	 
	3. PROJECT
	 	 	8	 
	4. OWNERSHIP OF PROJECT IP
	 	 	10	 
	5. MARKETING
	 	 	10	 
	6. ROYALTY
	 	 	11	 
	7. BOOKS AND RECORDS
	 	 	14	 
	8. EQUITY ISSUE
	 	 	15	 
	9. FURTHER FUNDING
	 	 	16	 
	10. ACCESS TO PRODUCT THROUGHOUT THE WORLD
	 	 	16	 
	11. COMPLIANCE WITH LAWS
	 	 	20	 
	12. PUBLICITY
	 	 	21	 
	13. WARRANTIES AND INDEMNITY
	 	 	22	 
	14. CONFIDENTIALITY
	 	 	24	 
	15. TERMS AND TERMINATION
	 	 	26	 
	16. CONSEQUENCES OF TERMINATION
	 	 	27	 
	17. WAIVER
	 	 	28	 
	18. ENTIRE AGREEMENT AND VARIATION
	 	 	29	 
	19. NOTICES
	 	 	29	 
	20. ASSIGNMENT
	 	 	30	 
	21. FORCE MAJEURE
	 	 	30	 
	22. DISPUTE RESOLUTION
	 	 	31	 
	23. SEVERANCE OF TERMS
	 	 	31	 
	24. NO PARTNERSHIP
	 	 	31	 






 









 






	 	 	 	 	 
	25. COSTS AND EXECUTION
	 	 	31	 
	26. THIRD PARTY RIGHTS
	 	 	32	 
	SCHEDULE 1 THE PROJECT
	 	 	34	 
	SCHEDULE 2 DOCUMENTS RELATING TO THE PERFORMANCE OF THE PROJECT
	 	 	35	 
	SCHEDULE 3 BACKGROUND INTELLECTUAL PROPERTY
	 	 	95	 
	SCHEDULE 4 MICROSCIENCE TERRITORY
	 	 	96	 
	SCHEDULE 5 MICROSCIENCE OPTION TERRITORY
	 	 	97	 
	SCHEDULE 6 PRESS RELEASE AND STATEMENT
	 	 	98	 






 









 






THIS
AGREEMENT is made and entered into as of
     day of March 2005



BETWEEN:





	(1)	 	THE WELLCOME TRUST LIMITED a company registered in England under number 2711000 as Trustee of
the Wellcome Trust, a charity registered in England under number 210183, whose registered
office is at 215 Euston Road, London NW1 2BE (the “Trust”); and
	 
	(2)	 	MICROSCIENCE HOLDINGS PLC a company registered in England and Wales under number 5106930
whose registered office is at 545 Eskdale Road, Winnersh, Wokingham, Berkshire, RG41 5TU
(“Microscience”); and
	 
	(3)	 	MICROSCIENCE LIMITED a company registered in England and Wales under number 3270465 whose
registered office is at 545 Eskdale Road, Winnersh, Wokingham, Berkshire, RG41 5TU
(“Microscience Limited”)





RECITALS:





	(A)	 	Microscience is a company which was incorporated in England as a private company limited by
            shares on 20th April 2004 under the provisions of the Companies Act 1985.
	 
	(B)	 	At the date of this Agreement, Microscience has an authorised share capital of £4,025,702
divided into [**] ‘A’ ordinary shares,
[**] ‘B’ ordinary shares, [**] ‘A’ preferred ordinary shares and [**] ‘B’ preferred ordinary shares of 5p each all of which have been issued fully
paid.
	 
	(C)	 	Microscience has invented or acquired a stable formulation for vaccines which may be suitable
for development of a novel, single-dose oral typhoid vaccine.
	 
	(D)	 	In order to further its charitable objectives, the Trust wishes to make a Programme Related
Investment by way of subscribing for ordinary shares in Microscience and providing further
funding to Microscience to undertake research and development of Microscience’s single-dose,
oral typhoid vaccine (“Award”).





1. INTERPRETATION





	 	 	In this Agreement and the Schedules to this Agreement, the following words and phrases shall
have the following meanings unless the context requires otherwise:
	 
	 	 	“Affiliate” means any entity that, directly or indirectly, through one or more
intermediates, is controlled by, controls, or is under common control with a specified
entity, and for the purposes of this definition:




1









 












	 	(a)	 	the term “control” means the possession of the power to direct or cause the
direction of the management and policies of an entity, whether by ownership of voting
stock by partnership interest, by contract or otherwise, including direct or indirect
ownership of more than fifty percent (50%) of the voting interest in the specified
entity; and
	 
	 	(b)	 	if at any time an entity no longer controls and is no longer controlled and is
no longer under the common control with a Party, this entity will no longer qualify as
an Affiliate of that Party as of that time and that Party will have no further
obligations on behalf of this former Affiliate under this Agreement;






	 	 	“Agreement” means this agreement;
	 
	 	 	“Application” means Microscience’s application to the Trust for a Strategic Translation
Award which is attached as Schedule 2;
	 
	 	 	“Articles” means the articles of association of Microscience, as amended from time to time;
	 
	 	 	“Background Intellectual Property” means:






	 	(a)	 	the patent applications and patents set out in Schedule 3 and all associated
Patent Rights, excluding any claims relating to the method known as signature tagged
mutagenesis;
	 
	 	(b)	 	the Background Know-How; and
	 
	 	(c)	 	any and all and copyright relating to typhoid vaccines owned or controlled by
Microscience at the Effective Date or at any time thereafter, but excluding the Project
Intellectual Property and excluding any copyright relating to the method known as
signature tagged mutagenesis;






	 	 	“Background Know-How” means any and all Know-How relating to the manufacture, development,
sale or other exploitation of Microscience’s typhoid vaccine which is actually used by
Microscience at the Effective Date or at any time thereafter, but excluding the Project
Intellectual Property; For the avoidance of doubt, “Background Know-How” does not include
any Know-How relating to the method known as signature tagged mutagenesis;
	 
	 	 	“Board” means the board of Directors of Microscience from time to time;
	 
	 	 	“Business Day” means a day other than Saturday, Sunday, bank or other public holiday in
England;
	 
	 	 	“Change of Control” means, in relation to any company, where a person (or persons acting in
concert) directly or indirectly, including through any subsidiary or holding company or
subsidiary or such holding company:




2









 












	 	(a)	 	has beneficial ownership over more than 50 per cent of the total voting rights
conferred by all the issued shares in the capital of that company which are ordinarily
exercisable in general meeting; or
	 
	 	(b)	 	has the right to appoint or remove a majority of its directors; or
	 
	 	(c)	 	has power to direct that the affairs of the company are conducted in accordance
with its wishes,






	 	 	in each case where such person or persons did not have such beneficial ownership, right or
power at the Effective Date;
	 
	 	 	“Combination Product” means a product that contains a Product together with one or more
other therapeutically or prophylactically active ingredient(s) that are sold either as a
fixed dose or as separate doses in a single package;
	 
	 	 	“Competent Authority” means any local or national agency, authority, department,
inspectorate, minister, ministry official or public or statutory person (whether autonomous
or not) of, or of any government of, any country having jurisdiction over this Agreement or
any of the Parties or over the development or marketing of vaccine products including the
European Commission and the European Court of Justice;
	 
	 	 	“Completion” means completion of the matters set out in Clause 2;
	 
	 	 	“Customer” means a third party;
	 
	 	 	“Directors” means the directors of Microscience appointed pursuant to the Articles;
	 
	 	 	“Documents” means paper, notebooks, books, files, ledgers, records, tapes, discs, diskettes,
CD-ROMs and any other media on which Know-How can be permanently stored;
	 
	 	 	“Effective Date” means the date of this Agreement as set out on page 1;
	 
	 	 	“Encumbrance” means any claim, charge, mortgage, security, lien, option, equity, power of
sale; hypothecation or other third party rights, retention of title, right of pre-emption,
right of first refusal or security interest of any kind;
	 
	 	 	“First Instalment” means the amount payable by the Trust to Microscience on Completion as
set out in Schedule 1;
	 
	 	 	“Force Majeure” means any event or circumstance which is beyond the reasonable control of
either Party, which the Party could not reasonably be expected to have taken into account at
the Effective Date and which results in or causes the failure of it to perform any or all of
its obligations under this Agreement, except that lack of funds shall not be interpreted as
a cause beyond the reasonable control of either Party;




3









 






	 	 	“Instalment” means the amount payable by the Trust to Microscience on the achievement by
Microscience of a Project Milestone on or before the relevant Project Milestone Date, as set
out in Schedule 1;
	 
	 	 	“Key Scientist” means a senior member of staff having sufficient knowledge and experience,
involved in performing Microscience’s obligations under this Agreement;
	 
	 	 	“Know-How” means unpatented technical and other information which is not in the public
domain including:






	 	a)	 	information comprising or relating to inventions, concepts, discoveries, data
(including, for the avoidance of doubt, data necessary or desirable for regulatory
submission), designs, formulae and ideas;
	 
	 	b)	 	information relating to Materials;
	 
	 	c)	 	methods, models, assays, research plans, procedures, designs for experiments
and tests;
	 
	 	d)	 	records and results of experimentation, testing research and development;
	 
	 	e)	 	processes including manufacturing process, specifications and techniques;
	 
	 	f)	 	drawings and manuals;
	 
	 	g)	 	instrumentation;
	 
	 	h)	 	chemical, pharmacological, toxicological, clinical, analytical and quality
control data;
	 
	 	i)	 	clinical trial data, data analyses, reports or summaries and information
contained in submissions to and information from regulatory authorities; and
	 
	 	j)	 	any Documents containing any of the foregoing






	 	 	and the fact that an item is known to the public shall not be taken to exclude the fact that
a compilation including the item, and/or a development relating to the item, is not known to
the public;
	 
	 	 	“Materials” means any chemical or biological substances including any:






	 	a)	 	nucleotide or nucleotide sequence including DNA and RNA sequences;
	 
	 	b)	 	organic or inorganic element or compound;
	 
	 	c)	 	protein including any peptide or amino acid sequence, enzyme, antibody or
protein conferring targeting properties and any fragment of a protein or a peptide
enzyme or antibody;




4









 






	 	d)	 	assay or reagent;
	 
	 	e)	 	cell line, culture medium;
	 
	 	f)	 	vaccine; or
	 
	 	g)	 	any other genetic or biological material;






	 	 	“Microscience Territory” means the countries and territories set out in Schedule 4;
	 
	 	 	“Microscience Option Territory” means the countries and territories set out in Schedule 5;
	 
	 	 	“Net Sales” means the gross invoiced amount billed for sales of Products to a Customer by
Microscience, its Affiliates or licensees, less the following items to the extent they are
paid or incurred or allowed and included in the invoice price:






	 	a)	 	quantity, trade and/or cash discounts or rebates actually granted or accrued;
	 
	 	b)	 	amounts repaid or credited and allowances including cash, credit or free goods
allowances, given by reason of billing errors, discounts, actually allowed or paid or
accrued;
	 
	 	c)	 	taxes, tariffs, customs duties and surcharges and other governmental charges
incurred in connection with the sale, exportation or importation of Products;






	 	 	provided that the transfer of Products by Microscience to Affiliates and licensees shall not
be considered a sale and in such cases, Net Sales shall be determined on the gross amount
invoiced by the Affiliate or licensee on the Customer, less the aforementioned deductions to
the extent they are allowed, paid or accrued;
	 
	 	 	“Parties” means Microscience and the Trust and “Party” shall mean either of them;
	 
	 	 	“Patent Rights” means patent applications, patents, author certificates, inventor
certificates, utility certificates, improvement patents and models and certificates of
addition and all foreign counterparts of them and includes all divisions, renewals,
continuations, continuations-in-part, extensions, reissues, substitutions, confirmations,
registrations, revalidations and additions of or to them, as well as any supplementary
protection certificate, or like form of protection in respect thereof;
	 
	 	 	“Product” means the oral typhoid vaccine developed by Microscience including all
formulations thereof but for the avoidance of doubt excluding spi-VEC Constructs;
	 
	 	 	“Project” means the programme of research and development relating to Microscience’s oral
typhoid vaccine as further described in the Application including the Project Milestones,
Project Milestone Dates and Instalments which are set out in Schedule 1;




5









 






	 	 	“Project Intellectual Property” means Know-How and copyright relating to oral typhoid
vaccines invented, created or produced by Microscience as a result of the performance of the
Project, together with all Patent Rights relating thereto;
	 
	 	 	“Project Materials” means Materials acquired, created, manufactured or used by Microscience
for, or during performance of, the Project;
	 
	 	 	“Project Milestone” means a milestone set out in Schedule 1, or as subsequently agreed in
writing between the Parties, the achievement of which by Microscience on or before the
relevant Project Milestone Date, shall trigger the payment to Microscience of the relevant
Instalment by the Trust;
	 
	 	 	“Project Milestone Criteria” means the objective criteria agreed between the parties and set
out at Schedule 1 for determining whether a Project Milestone has been met;
	 
	 	 	“Project Milestone Date” means a date for the achievement of a Project Milestone as set out
in Schedule 1, or as subsequently revised to a later date in accordance with Clause 3.2;
	 
	 	 	“Quarter” means a period of three consecutive calendar months commencing on 1 January, 1
April, 1 July or 1 October in any year and “Quarterly” shall be construed accordingly;
	 
	 	 	“Royalty” means the sums payable by Microscience to the Trust or by the Trust to
Microscience under Clauses 6.1, 6.2 and 6.3;
	 
	 	 	“Second Instalment” means the amount payable by the Trust to Microscience on the achievement
by Microscience of the Second Project Milestone on or before the relevant Second Project
Milestone Date, as set out in Schedule 1;
	 
	 	 	“Shareholder” means a holder of shares in the capital of Microscience;
	 
	 	 	“Shares” means A ordinary shares of £0.05 each in the capital of Microscience;
	 
	 	 	“Site Visit Group” means the group of people appointed by the Trust in accordance with
Clause 3.11;
	 
	 	 	“spi-VEC Constructs” means constructs based on the attenuated typhoid bacterium developed by
Microscience that have been further engineered to deliver non-typhoid related antigens;
	 
	 	 	“Subscription Shares” means the Shares to which the Trust is entitled to subscribe pursuant
to Clauses 8.1 and 8.2;
	 
	 	 	“Third Instalment” means the amount payable by the Trust to Microscience on the achievement
by Microscience of the Third Project Milestone as set out in Schedule 1;




6









 






	 	 	“Trust Direct Costs” means any costs and expenses directly incurred by the Trust in respect
of the commercialisation of the Product, including cost of goods, manufacturing costs, costs
of delivery, marketing costs, distribution costs and regulatory costs;
	 
	 	 	“Trust Indirect Costs” means any reasonable costs and expenses incurred by the Trust in
respect of the commercialisation of the Product other than Trust Direct Costs, including by
way of example, costs of an educational health awareness campaign or professional costs
incurred in negotiations with governments beyond the normal regulatory process;
	 
	 	 	“Trust Net Receipts” means, in relation to any individual Product, the monetary amount
received by the Trust which is attributable to sale of that Product by it, its Affiliates or
licensees after deduction of Trust Indirect Costs but prior to deduction of the Trust Direct
Costs which are attributable to the sale of the relevant Product, and
	 
	 	 	“Trust Territory” means those countries and territories which become part of the Trust
Territory pursuant to the provisions of Clauses 10.4, 10.5, 10.6, 10.7 or 10.8.
	 
	1.1	 	In this Agreement:






	 	1.1.1	 	unless the context otherwise requires, all references to a particular Clause
or Schedule shall be a reference to that clause in, or schedule to, this Agreement, as
it may be amended from time to time pursuant to this Agreement;
	 
	 	1.1.2	 	the table of contents and headings are inserted for convenience only and shall
be ignored in construing this Agreement;
	 
	 	1.1.3	 	unless the contrary intention appears, words importing the masculine gender
shall include the feminine and vice versa and words in the singular include the plural
and vice versa;
	 
	 	1.1.4	 	any reference to persons includes natural persons, firms, partnerships,
limited liability partnerships, companies, corporations, unincorporated associations,
local authorities, governments, states, foundations and trusts (in each case whether or
not having separate legal personality) and any agency of any of the above;
	 
	 	1.1.5	 	any phrase introduced by the terms “including”, “include”, “in particular” or
any similar expression shall be construed as illustrative and shall not limit the sense
of the words preceding those terms;
	 
	 	1.1.6	 	any reference to a statute, statutory provision or subordinate legislation
(“Legislation”) (except where the context otherwise requires);






	 	1.1.6.1	 	shall be deemed to include any bye-laws, licences, statutory
instruments, rules, regulations, orders, notices, directions, consents or
permissions made under that Legislation; and




7









 






	 	1.1.6.2	 	shall be construed as referring to any Legislation which replaces,
re-enacts, amends or consolidates such Legislation (with or without
modification) at any time;






	 	1.1.7	 	any reference to an English legal expression for any action, remedy, method of
judicial proceeding, legal document, legal status, court, official or any legal concept
or thing shall, in respect of any jurisdiction other than England, be deemed to include
a reference to what most nearly approximates in that jurisdiction to the English legal
expression;
	 
	 	1.1.8	 	any reference to a Party includes a reference to their respective
successors-in-title and permitted assignees;
	 
	 	1.1.9	 	any obligation imposed upon Microscience may be satisfied by Microscience or
by its wholly owned subsidiary, Microscience Limited; and
	 
	 	1.1.10	 	any statement that a licence is granted or is to be granted by Microscience shall
mean that the licence is granted or is to be granted by Microscience or Microscience
Limited.





2. COMPLETION





	2.1	 	Completion shall take place immediately following execution of this Agreement by both
Parties.
	 
	2.2	 	The Trust shall pay to Microscience the First Instalment within ten (10) Business Days of
Completion.





3. PROJECT





	3.1	 	Microscience shall further develop a single-dose, oral typhoid vaccine in accordance with the
work plan set out in the Application and shall use its reasonable endeavours to achieve each
Project Milestone on or before the relevant Project Milestone Date. The Parties acknowledge
that unforeseen circumstances and technical issues can affect the progress of any scientific
research and development work and could delay the achievement of any of the Project
Milestones.
	 
	3.2	 	Microscience hereby undertakes diligently to perform the research and development work and
other tasks, including project management of the Project, as set out in the Application. In
the event that Microscience fails to achieve a Project Milestone on or before the relevant
Project Milestone Date, the Parties shall meet to discuss the matter and, provided
Microscience has acted diligently in its work towards the Project Milestone, the Parties shall
change the relevant Project Milestone Date to a later date which would, realistically, give
Microscience sufficient time to achieve the Project Milestone by the new date.
	 
	3.3	 	If there is any disagreement between the Application and the terms of this Agreement, the
terms of this Agreement shall prevail.




8









 






	3.4	 	Microscience undertakes to use all funding received from the Trust pursuant to this
Agreement solely for the purposes of the Project. Microscience shall obtain the Trust’s
prior written consent to any other use of any funding received from the Trust pursuant to
this Agreement.
	 
	3.5	 	Upon achievement by Microscience of a Project Milestone in accordance with the Project
Milestone Criteria on or before the relevant Project Milestone Date, Microscience shall notify
the Trust of such achievement in writing (“Project Milestone Notice”). The Project Milestone
Notice shall specify the relevant Project Milestone and shall give reasonable details as to
how the specified Project Milestone has been achieved.
	 
	3.6	 	If Microscience has achieved the relevant Project Milestone by the relevant Project Milestone
Date, the Trust shall, within thirty (30) days of receipt of an invoice from Microscience, pay
the relevant Instalment set out in Schedule 1 to Microscience by transfer of funds to the bank
account referred to in Clause 6.8.
	 
	3.7	 	If the Trust believes that Microscience has not achieved the specified Project Milestone on
or before the relevant Project Milestone Date, it shall, within thirty (30) days of receipt of
the relevant invoice, inform Microscience of its reasons and the Parties shall meet to discuss
the matter. If the Parties fail to settle the matter at such meeting, the matter shall be
dealt with in accordance with the procedure set out in Clause 22.
	 
	3.8	 	At the end of each Quarter following the Effective Date, Microscience shall provide the Trust
with a summary written report on the progress made and results obtained in performance of the
Project during that Quarter.
	 
	3.9	 	As and when required, but not less than twice per calendar year, the Head of Business
Development, Technology Transfer Division of the Trust or his nominee and Rod Richards, Chief
Executive Officer of Microscience, shall meet to discuss the progress made by Microscience on
the Project.
	 
	3.10	 	The obligations of Clauses 3.1, 3.2, and 3.4 shall be considered to be material obligations
for the purposes of Clause 15.
	 
	3.11	 	The Trust at its sole cost, shall be entitled to establish and appoint up to four members of
a group (“Site Visit Group”) which, upon reasonable notice to Microscience, shall be permitted
twice per calendar year to visit each of Microscience’s facilities where Project work is being
carried out and sites where any Project clinical trials are being conducted and meet a Key
Scientist for the purpose of updating the Trust on the progress of the Project. Microscience
may suggest to the Trust appropriate candidates for appointment to the Site Visit Group, but
the decision to appoint, or replace, any individual shall be at the Trust’s sole discretion.
	 
	3.12	 	At the Effective Date, the Key Scientist is [**]. If Microscience intends to appoint an
additional Key Scientist or a replacement for a Key Scientist involved in performing
Microscience’s obligations under this Agreement, it shall, prior to such appointment, seek the
Trust’s written approval to the appointment. However the Trust shall not unreasonably
withhold its consent to such an appointment.




9









 











4. OWNERSHIP OF PROJECT IP





	4.1	 	All Project Intellectual Property (including data produced in the course of performing the
Project) shall be owned solely by Microscience.
	 
	4.2	 	Microscience shall be responsible, at its sole cost, for filing, prosecuting and maintaining
all Patents Rights which are Project Intellectual Property. Microscience shall consult the
Trust on all material aspects of the filing, prosecution and maintenance of such Patent Rights
and shall consider in good faith all reasonable representations made by the Trust in relation
thereto. Microscience shall keep the Trust informed of all Patent Rights which are Project
Intellectual Property and which are granted and the progress of all applications relating to
those Patent Rights.
	 
	4.3	 	If Microscience chooses not to pursue filing, prosecution or maintenance of any Patent Rights
which are Project Intellectual Property in any country, it shall immediately notify the Trust
of this fact in writing. The Trust shall be entitled, but not obliged, at its own cost, to
pursue or maintain such Patent Rights in the relevant country or countries in Microscience’s
name and, subject to payment by the Trust of Microscience’s reasonable costs, Microscience
shall provide such assistance to the Trust as may be reasonably be required by the Trust.
	 
	4.4	 	Microscience shall not enforce its rights under any Project Intellectual Property for
infringement or potential infringement by:






	 	4.4.1	 	any not-for-profit or charitable organisation which is conducting
non-commercially sponsored research;
	 
	 	4.4.2	 	any person carrying out non-commercially sponsored research on behalf of any
not-for-profit or charitable organisation.






	4.5	 	This Clause 4 shall not prevent Microscience enforcing its rights under any Background
Intellectual Property.
	 
	4.6	 	Microscience hereby grants to the Trust a non-exclusive, worldwide, royalty-free, perpetual,
irrevocable, sub-licenseable licence under all its right, title and interest in and to the
Project Intellectual Property to conduct non-commercial research.





5. MARKETING





	5.1	 	To the extent that it is commercially viable to do so, Microscience shall use its reasonable
endeavours, itself or through its Affiliates or licensees, to:






	 	5.1.1	 	advertise, promote, demonstrate, market, sell and distribute the Product in
the Microscience Territory;
	 
	 	5.1.2	 	maximise the use, sales and penetration in the market of the Product in the
Microscience Territory; and




10









 






	 	5.1.3	 	actively promote and develop market opportunities for the Product in the
Microscience Territory.






	 	 	For the avoidance of doubt the costs of the activities described in this Clause 5.1 shall
not be borne by the Trust.
	 
	5.2	 	The Trust shall use its reasonable endeavours throughout the Trust Territory to ensure that
it fulfils its charitable objectives by taking such action as it reasonably anticipates will
result in a substantial uptake of the Product in the Trust Territory. For the avoidance of
doubt the costs of the activities described in this Clause 5.2 shall not be borne by
Microscience.





6. ROYALTY





	6.1	 	Microscience shall pay the Trust a Royalty of [**]% of all lump sum or milestone payments
received by Microscience in connection with the grant of any licence to a third party to
develop, manufacture, sell, distribute or supply the Product, where such lump sum or milestone
payments are payable upon the signature of the agreement granting the licence or are payable
upon the achievement of technical development milestones prior to the first commercial sale of
the Product.
	 
	6.2	 	Microscience shall pay the Trust a Royalty on all worldwide Net Sales of Product by
Microscience, its Affiliates and licensees (excluding sales to or by the Trust or its
Affiliates) during the first ten years following the end of the first Quarter in which the
first invoices to Customers for sales of Product became due, as follows. Where such Net Sales
in any calendar year are less than US$ [**], the Royalty rate shall be [**]%. Where such Net
Sales in any calendar year are greater than US$ [**], the Royalty rate shall be [**]% for the
first US$ [**] of Net Sales, [**]% for the Net Sales in the range US$ [**] to US$ [**] and
[**]% for any Net Sales in excess of US$ [**] in the calendar year concerned.
	 
	6.3	 	The Trust shall pay Microscience a Royalty of [**]% of Trust Net Receipts during the first 10
years following the end of the first Quarter in which the first Product is made available by
the Trust, its Affiliates or licensees.
	 
	6.4	 	If:






	 	6.4.1	 	any sale or other disposal of Product by Microscience, its Affiliates or its
licensees to a third party is other than in a bona fide arm’s length transaction
exclusively for money; or
	 
	 	6.4.2	 	any Product is sold or disposed of by Microscience, its Affiliates or its
licensees or allowed by Microscience, its Affiliates or its licensees to be used for
consideration other than cash,






	 	 	then such sale, disposal or use shall be deemed to be a sale for the purposes of Clause 6.2
at the relevant open market price in the country in which the sale, disposal or use occurs.
If such open market price is not ascertainable, a reasonable price shall be assessed based




11









 






	 	 	on an arm’s length basis or the value of the goods or services provided in exchange for the
supply of the Product.
	 
	6.5	 	With respect to Combination Products sold or disposed of by Microscience, its Affiliates or
licensees, the Net Sales used for the calculation of the Royalties under Clause 6.2 shall be
determined as follows:
	 
	 	 	A/(A+B) x (Net Sales of the Combination Product), where:






	 	A=	 	standard sales price of the Product, containing the same
amount of the oral typhoid vaccine as the sole active ingredient as the
Combination Product in question, in the given country; and
	 
	 	B= 	 	standard sales price of the ready-for-sale form of a product
containing the same amount of the other therapeutically active
ingredient(s) that is contained in the Combination Product in question,
in the given country






	 	 	provided that if, in a specific country: (a) the other therapeutically active ingredient(s)
in such Combination Product are not sold separately in such country, Net Sales shall be
adjusted by multiplying actual Net Sales of such Combination Product by the fraction A/C,
where C is the standard sales price in such country of such Combination Product; and (b) if
a Product is not sold separately, Net Sales shall be calculated by multiplying actual Net
Sales of such Combination Product by the fraction (C-B)/C, where B is the standard sales
price in such country of the other therapeutically active ingredient(s) in the Combination
Product and C is the standard sales price in such country of the Combination Product. The
standard sales price for the Product and for each other active ingredient shall be for a
quantity comparable to that used in such Combination Product and of the same class, purity
and potency. If, in a specific country, both a Product and a product containing the other
active ingredients in such Combination Product are not sold separately, a market price for
such Product and such other active ingredients shall be negotiated by the Parties in good
faith based upon the costs, overhead and profit as are then incurred for such Combination
Product and all products then being made and marketed by Microscience and having an
ascertainable market price that are comparable to such Product or such other active
ingredients, as applicable. If, in a specific country, the foregoing calculations do not
fairly represent the value of the various active ingredients included in a Combination
Product, the allocation of Net Sales for such Combination Product shall be negotiated by the
Parties in good faith.
	 
	6.6	 	The Parties acknowledge that Microscience may be liable to pay royalties and make other
payments to third parties in respect of the development, manufacture or sale of Product and
that the Trust may be liable to pay royalties and make other payments to third parties in
respect of the manufacture or sale of Product. The Parties agree that each Party shall be
solely responsible, at its own cost, for all such payments to third parties and any Royalties
payable under this Agreement shall not be reduced as a consequence.




12









 






	6.7	 	Unless otherwise agreed between the Parties in writing, all
payments due to the Trust under this Agreement shall be made in
pounds sterling to the following account:





	 	 	 	 	 
	 

	 	Account Name:
	 	The Wellcome Trust
	 

	 	Account Number:
	 	[**]
	 

	 	Bank:
	 	HSBC Bank Plc
	 

	 	Sort Code:
	 	40-03-28
	 

	 	Swift:
	 	MIDLGB21
	 

	 	Branch Address:
	 	31 Holborn Circus, London, EC1N 2HR.







	6.8	 	Unless otherwise agreed between the Parties in writing, all payments due to Microscience
under this Agreement shall be made in pounds sterling to the following account:





	 	 	 	 	 
	 

	 	Account Name:
	 	MICROSCIENCE LIMITED
	 

	 	Account Number:
	 	[**]
	 

	 	Bank:
	 	BARCLAYS
	 

	 	Sort Code:
	 	20-72-17
	 

	 	Branch Address:
	 	Richmond & Twickenham Business Centre,
PO BOX 13, 8 George Street Richmond, TW9 1JU







	6.9	 	Within 150 days of the end of each Quarter, each Party shall deliver a statement to the other
Party setting out all sales of Product made in the relevant Quarter by that Party, its
Affiliates and licensees and the amount of Royalty which is due to the other Party (“Quarterly
Statement”). Each Party shall deliver to the other Party an invoice for the amount due to it
as set out in the Quarterly Statement. The Royalty amount invoiced shall be payable to the
other Party within thirty days of receipt of the invoice.
	 
	6.10	 	Where sales of Product on which Royalty payments are payable under Clauses 6.1, 6.2 or 6.3
are invoiced or calculated in a currency other than pounds sterling, conversion into pounds
sterling shall be calculated by reference to the relevant foreign exchange selling rate for
the currency in which they are invoiced or calculated of the Financial Times newspaper at the
close of business in London on the last day of the Quarter to which the Royalty relates.
	 
	6.11	 	If either Party does not receive payment of any sums due to it under this Clause 6 within the
time specified, interest shall accrue on such sums at the rate equivalent to three per cent
(3%) per annum over the then current base rate of HSBC bank, calculated on a daily basis.
	 
	6.12	 	If, for any reason, either Party (“Payee”) does not receive by the due date any amount due to
it from the other Party (“Payer”) in accordance with the terms of this Agreement, the Payee
shall be entitled to off-set the amount due (together with any interest payable thereon in
accordance with Clause 6.11) against any amount which the Payee is due to pay to the Payer.




13









 






	6.13	 	All payments under this Agreement are expressed to be exclusive of goods, sales, value added
or any similar tax (“Value Added Tax”) howsoever arising, and the Party obliged to make
payment shall pay the other Party, in addition to those payments, all Value Added Tax for
which the other Party is liable to account to any Competent Authority in relation to any
supply made or deemed to be made for Value Added Tax purposes pursuant to this Agreement.
The Party obliged to make payment shall pay any payments due to the other Party under this
Clause 6.13 at the same time as the relevant payment is due under this Agreement.
	 
	6.14	 	If either Party is required by law to make any withholding or similar tax payment on behalf
of the other Party, with respect to any of the payments to be made to the other Party under
this Agreement, the amount of such required withholding or tax payment shall be deducted from
the amount of payments otherwise due to the other Party and paid or deposited by the paying
Party in accordance with the applicable law.
	 
	6.15	 	With respect to such deduction and payment of any withholding or similar taxes required under
clause 6.14, the paying Party shall provide such assistance to the other Party as may be
reasonably necessary to enable or assist the other Party to claim exemption therefrom or (if
that is not possible) to obtain a credit for the deduction or withholding under any applicable
double taxation or similar agreement from time to time in force, and shall provide the other
Party with proper evidence as to the payment of such tax.
	 
	6.16	 	The obligation on each Party to pay the other Party the Royalties in accordance with Clauses
6.1, 6.2 and 6.3 shall be material obligations of this Agreement for the purposes of Clause
15.





7. BOOKS AND RECORDS





	7.1	 	Each Party shall:






	 	7.1.1	 	keep true and accurate records and books of account for six years following
the end of the calendar year to which they relate; and
	 
	 	7.1.2	 	procure that its Affiliates and licensees shall keep true and accurate records
and books of account for three years following the end of the calendar year to which
they relate,






	 	 	which contain all data necessary for the calculation of the Royalties payable by it to the
other Party (“Books”).
	 
	7.2	 	Once per calendar year following the Effective Date, each Party may request that an
independent accountant of its choice be allowed to certify any Quarterly Statements of the
other Party, provided always that each individual Quarterly Statement may be certified only
once.
	 
	7.3	 	Each Party shall, and shall procure that its Affiliates and licensees shall, make available
to the independent accountant all Books which are required for the purpose of certifying the
relevant Quarterly Statement, provided that the independent accountant agrees to be




14









 






	 	 	bound by terms of confidentiality and non-use which are no less onerous than the terms of
Clause 14. The Quarterly Statements so certified shall be final and binding between the
Parties.
	 
	7.4	 	If any Quarterly Statement is shown to have underestimated the monies payable by more than
five percent (5%), the cost of the certification shall be the responsibility of the Party
shown to have underpaid. Otherwise, the cost shall be the responsibility of the Party
requesting the certification.
	 
	7.5	 	Any outstanding payments which are identified as a result of carrying out the certification
(including interest payments thereon under Clause 6.11) shall be paid immediately.





8. EQUITY ISSUE





	8.1	 	In consideration of and upon payment of the First Instalment being made by the Trust,
Microscience shall, subject to obtaining any necessary regulatory approvals, within 45 days of
the date of payment, allot and issue to the Trust [**] Shares. The nominal subscription price
for such Shares shall be £[**] per Subscription Share. Microscience undertakes to obtain any
regulatory approvals required for the issue of the Subscription Shares as soon as practicable.
	 
	8.2	 	In consideration of and upon payment of the Third Instalment being made by the Trust,
Microscience shall, subject to obtaining any necessary regulatory approvals, within 45 days of
the date of payment, allot and issue to the Trust [**] Shares. The nominal subscription price
for such Shares shall be £[**] per Subscription Share. Microscience undertakes to obtain any
regulatory approvals required for the issue of the Subscription Shares as soon as practicable.
	 
	8.3	 	Microscience warrants that it has obtained all board, shareholder and other approvals and
consents required for it to enter into this Agreement and issue the Subscription Shares to the
Trust in accordance with this Agreement.
	 
	8.4	 	If Microscience Shares are admitted to trading on the Alternative Investment Market of the
London Stock Exchange, the main London Stock Exchange or any recognised investment exchange
and such admission becomes effective in accordance with the relevant rules of the London Stock
Exchange (or relevant recognised exchange), Microscience shall ensure that all Shares allotted
to, or to be allotted to, the Trust in accordance with this Agreement are also admitted to
trading on the Alternative Investment Market of the London Stock Exchange, the main London
Stock Exchange or the relevant recognised investment exchange, as the case may be. In
connection with the admission to trading, Microscience shall provide such information and
documents, pay all fees and execute and deliver all such documents as shall be necessary and
shall generally do and procure to be done all such things as may properly be required so as to
enable admission to take place.




15









 











9. FURTHER FUNDING





	9.1	 	In Microscience’s first investment round subsequent to the Effective Date, where such round
is led by an institutional investor, or venture capital fund manager that is a member of the
British Venture Capital Association or an overseas equivalent, Microscience may propose (but
is not obliged to propose) that the Trust participate in such investment round in an amount
not exceeding ten per cent (10%) of such investment round. If Microscience makes such a
proposal, it shall do so when the terms of the investment round have been agreed with other
potential investors. If the Trust participates in the investment round, the Trust shall
subscribe for the same class of shares at the same price per share as other investors, or
enter into an instrument convertible into shares on the same terms as other investors. For
this purpose, the Company will provide the Trust access to Company information that is
appropriate for a potential investor.
	 
	9.2	 	If Microscience wishes to raise further funding in respect of the Project, it shall promptly
inform the Trust in writing, including reasonable details of the funding required, and may
make an application to the Trust for funding. The Trust will consider such application but,
for the avoidance of doubt, shall have no obligation to grant Microscience any further
funding.





10. ACCESS TO PRODUCT THROUGHOUT THE WORLD





	10.1	 	The Parties have agreed to divide the world into the Microscience Territory, the Microscience
Option Territory and the Trust Territory.
	 
	10.2	 	Microscience shall have the sole right, itself or through its Affiliates or licensees, to
make, have made, sell, offer to sell, use, import, export and keep Product in the Microscience
Territory.
	 
	10.3	 	Except as provided in Clause 10.11, Microscience shall have the sole right, itself or through
its Affiliates or licensees, to make, have made, sell, offer to sell, use, import, export and
keep Product in the Microscience Option Territory.
	 
	10.4	 	Subject to Clause 10.6, if within the period of [**] years commencing on the date of the
first commercial sale of Product anywhere in the world (the “[**] Year Period”), Microscience
has not:






	 	10.4.1	 	provided the Trust with a credible business plan which provides for the sale of
Product in any particular country within the Microscience Option Territory (which
Microscience intends to implement within [**] years of delivery of its business plan to
the Trust); or
	 
	 	10.4.2	 	granted a licence to a third party which provides for the sale of Product in any
particular country within the Microscience Option Territory; or
	 
	 	10.4.3	 	sold Product in any particular country within the Microscience Option Territory




16









 






	 	 	 	and the Trust provides Microscience with a credible business plan providing for
sale of Product in that country (which the Trust intends to implement), that
country shall cease to be part of the Microscience Option Territory and shall be
deemed to be part of the Trust Territory. [**] months after the commencement of
the [**] year period referred to in Clause 10.4.1, Microscience shall, upon
request by the Trust, report on its progress towards implementing the business
plan in the country concerned.






	10.5	 	If Microscience decides, at any time during the [**] year period referred to in Clause
10.4.1, that it is no longer interested in commercialising Product in the country concerned,
it shall forthwith inform the Trust accordingly and, if the Trust provides Microscience with a
credible business plan providing for sale of Product in that country (which the Trust intends
to implement), that country shall cease to be part of the Microscience Option Territory and
shall be deemed to be part of the Trust Territory.
	 
	10.6	 	With respect to any particular country within the Microscience Option Territory, Microscience
may extend the [**] Year Period set out in Clause 10.4 to a period of [**] years commencing on
the date of the first commercial sale of Product anywhere in the world by giving written
notice to the Trust within the [**] Year Period, provided that:






	 	10.6.1	 	Microscience shall not unreasonably exercise its right to extend the [**] Year Period
and thereby block the Trust’s access to the relevant country for the two year extension
period; and
	 
	 	10.6.2	 	Microscience demonstrates every six months during the two year extension of the [**]
Year Period that it is taking steps towards the sale of Product in the relevant country
at a reasonable rate. If the Parties do not agree on whether Microscience has
satisfied the requirements of this sub-clause 10.6.2, the dispute shall be resolved in
accordance with Clause 22.






	10.7	 	If no commercial sale of a Product has taken place in any country in the Microscience
Territory or the Microscience Option Territory within the period of 12 years commencing on the
Effective Date and Microscience has not:






	 	10.7.1	 	provided the Trust with a credible business plan which provides for the sale of
Product in any particular country within the Microscience Option Territory (which
Microscience intends to implement within [**] months of delivery of its business plan
to the Trust); or
	 
	 	10.7.2	 	granted a licence to a third party which provides for the sale of Product in any
particular country within the Microscience Option Territory






	 	 	and the Trust provides Microscience with a credible business plan providing for sale of
Product in that country (which the Trust intends to implement), that country shall be deemed
to be part of the Trust Territory and shall no longer be part of the Microscience Option
Territory.
	 
	10.8	 	If Microscience terminates this Agreement under the provisions of Clause 15.3 and
Microscience has not:




17









 












	 	10.8.1	 	granted a licence to a third party which provides for the sale of Product in any
particular country within the Microscience Option Territory; or
	 
	 	10.8.2	 	sold Product in any particular country within the Microscience Option Territory






	 	 	and the Trust provides Microscience with a credible business plan providing for sale of
Product in that country (which the Trust intends to implement), that country shall cease to
be part of the Microscience Option Territory and shall be deemed to be part of the Trust
Territory.
	 
	10.9	 	The Trust may at any time propose that it be licensed to commercialise the Product in
countries of the Microscience Territory on such terms as the Trust wishes to put forward but
Microscience shall not have any obligation to agree to any such proposals or to discuss or
negotiate with the Trust concerning such proposals.
	 
	10.10	 	Microscience hereby grants to the Trust, subject to the provisions of this Agreement, a
licence under the Project Intellectual Property and the Background Intellectual Property to:






	 	10.10.1	 	make, dispose of, offer to dispose of, use and keep Product in the Trust Territory
and to import and export Product between countries in the Trust Territory; and
	 
	 	10.10.2	 	carry out commercial research and development in relation to the manufacture of the
Product in any countries in the Trust Territory and the Microscience Option Territory.
For the avoidance of doubt, the Trust shall not have any rights under this Agreement to
perform signature tagged mutagenesis.






	 	 	The licence granted under Sub-Clause 10.10.1 shall be an exclusive licence of Microscience’s
rights under the Project Intellectual Property and the Background Intellectual Property for
the purposes mentioned in Sub-Clause 10.10.1 and the licence granted under Sub-Clause
10.10.2 shall be non-exclusive. The Trust may make Product in the Microscience Territory if
it obtains Microscience’s prior written consent, but Microscience shall not have any
obligation to grant such consent.
	 
	10.11	 	In the event that the Trust wishes to manufacture and keep Product in a country of the
Microscience Option Territory or the Trust wishes to transport Product through a country of
the Microscience Option Territory solely for the purposes of exporting that Product to, and
using and disposing of that Product in, countries of the Trust Territory, the Trust shall
notify Microscience accordingly. Provided that:
	 
	 	 	     (a) it would be lawful under the laws of that country for Microscience to grant a
licence to the Trust under the Project Intellectual Property and the Background Intellectual
Property allowing the Trust to manufacture and keep the Product in that country (or allowing
the Trust to transport Product through that country) solely for export and prohibiting the
Trust and any sub-licensees from selling, using or disposing of the Product in that country;
and




18









 






	 	 	     (b) such restrictions on the license would be effective and enforceable under the laws
of that country.
	 
	 	 	Microscience shall, within 45 days of receipt of such notification from the Trust, grant a
licence to the Trust under the Project Intellectual Property and the Background Intellectual
Property allowing the Trust to manufacture and keep the Product in the country concerned
solely for export to the Trust Territory (or allowing the Trust to transport Product through
that country) but prohibiting the Trust and any sub-licensees from selling, using or
disposing of the Product in the country concerned.
	 
	 	 	In the event that the provisos set out in sub-paragraphs (a) and (b) of this Clause 10.11
are no longer satisfied in the country concerned, any licence granted pursuant to this
Clause 10.11 shall immediately terminate in the country concerned.
	 
	10.12	 	The licence granted under Clause 10.10 and any licence that may be granted under Clause
10.11 shall continue until the expiry of the last to expire of the Patents Rights comprised in
the Project Intellectual Property and the Background Intellectual Property in each country in
the Trust Territory and the Microscience Option Territory.
	 
	10.13	 	Subject to Clause 10.14, the Trust shall be entitled to sub-license its rights under Clause
10.10 and any rights that are granted to the Trust pursuant to Clause 10.11.
	 
	10.14	 	In relation to any sub-licence:






	 	10.14.1	 	the Trust shall promptly notify Microscience of the execution of any sub-licence
agreement and shall at the request of Microscience promptly provide Microscience with a
true and complete copy of the sub-licence agreement;
	 
	 	10.14.2	 	the provisions contained in any sub-licence agreement shall be consistent with the
provisions of this Agreement;
	 
	 	10.14.3	 	the sub-licence agreement shall prohibit further sub-licensing by the sub-licensee
provided that further sub-licensing shall be permitted with Microscience’s prior
written consent, but Microscience shall not have any obligation to grant such consent,
and
	 
	 	10.14.4	 	the Trust shall at all times ensure the observance and performance by each
sub-licensee of the provisions of the sub-licence and indemnify Microscience against
any loss, damages, costs, claims or expenses which are awarded against or incurred by
Microscience as a result of any breach by any sub-licensee of any of the provisions of
the sub-licence, as if the breach had been that of the Trust.






	10.15	 	Microscience shall:






	 	10.15.1	 	upon request, deliver to the Trust, or to a person nominated by the Trust (if that
person has entered into a confidentiality agreement with Microscience), all Know-How
comprised in the Project Intellectual Property, Background Know-




19









 






	 	 	 	How and Materials reasonably required by the Trust to exercise the Trust’s
rights under the licence granted under Clause 10.10; and
	 
	 	10.15.2	 	upon request, provide to the Trust, or to a person nominated by the Trust (if that
person has entered into a confidentiality agreement with Microscience), at the Trust’s
sole cost, at least 24 person-days of scientific support at the Trust’s or the
nominated person’s premises, at a time mutually agreed between the Parties to enable
the Trust to exercise its rights under the licence granted under Clause 10.10. The
Trust shall pay to Microscience within 30 days of receipt of an invoice from
Microscience the costs of such scientific support charged at industry standard rates
plus overhead and any necessary travelling and hotel expenses relating to such
scientific support.






	10.16	 	Microscience shall have the option of proposing that it supplies the Trust’s requirements of
Product for distribution within the Trust Territory at a price or at prices to be agreed
between the Parties, but Microscience shall have no obligation to supply Product to the Trust
and the Trust shall have no obligation to purchase Product from Microscience.
	 
	10.17	 	Product produced and distributed by the Trust, its Affiliates or licensees in the Trust
Territory shall be manufactured according to the same manufacturing process, and shall be
comparable to, Product produced and sold by Microscience, its Affiliates or licensees in the
Microscience Territory. Determinations of Product comparability shall be based on the product
release and characterisation specifications and associated assays that Microscience uses to
release its own Product. All costs associated with determining Product comparability
(including the costs of the necessary transfer of assays) shall be borne by the Trust. If
Microscience, its Affiliates or licensees discontinue the manufacture and sale of the Product
due to termination of this Agreement, the Product produced and distributed by the Trust, its
Affiliates or licensees shall be an oral typhoid vaccine (excluding spi-VEC Constructs).
Product sold or supplied by the Trust, its Affiliates or licensees shall have packaging which
is substantially different from that used by Microscience (save that the Trust shall not be
obliged to make alterations to its existing packaging if Microscience changes its own
packaging), and shall be labelled with the words “Product sold under licence from Microscience
Holdings PLC.”
	 
	10.18	 	Microscience hereby grants to the Trust a non-exclusive, royalty free, sub-licenseable
licence throughout the Trust Territory, for a period of time equivalent to the term of the
licence granted to the Trust under Clause 10.10, to use Microscience’s trade mark
“MICROSCIENCE” solely to label Product with the wording given in Clause 10.17 in order to
comply with the provisions of Clause 10.17.





11. COMPLIANCE WITH LAWS





	11.1	 	Each Party shall ensure that each employee working on the Project or performing other
obligations under this Agreement is employed under a contract compliant with all relevant laws
and regulations.




20









 






	11.2	 	Microscience shall be responsible for the management, monitoring and control of all
research, development, regulatory, commercialisation, marketing, distribution and sales work
undertaken pursuant to this Agreement except where the Trust undertakes any such work in
accordance with Clauses 5.2 or 10. In performing the obligations imposed on it by this
Agreement, each Party shall comply with the requirements of all applicable laws and
regulatory authorities governing the use of radioactive isotopes, animals, pathogenic
organisms genetically modified organisms (GMOs), toxic and hazardous substances, research on
human subjects and human embryos, and include appropriate ethical approvals and consents,
including for example but not limited to, such approvals and consents for obtaining tissues
and other human samples.
	 
	11.3	 	Except in accordance with Clauses 5.2 and 10, the Trust shall have no obligation, express or
implied, to supervise, monitor, review or otherwise assume responsibility for the production,
manufacture, testing, marketing, sale or disposal of any Product.





12. PUBLICITY





	12.1	 	Microscience shall not use the “Wellcome Trust” name or logo except with the prior written
consent of the Trust and in the manner approved by the Trust and the Trust shall not use the
name or logo of Microscience except with the prior written consent of Microscience and in the
manner approved by Microscience.
	 
	12.2	 	Neither Party shall disclose any of the terms of this Agreement to any person other than to
its professional advisors, except that Microscience may disclose the terms of this Agreement
to other persons to the extent required in connection with any fundraising of Microscience and
provided Microscience makes such disclosure under terms of confidentiality.
	 
	12.3	 	Subject to Clauses 12.4 and 12.5, neither Party may issue any press release or public
announcement regarding this Agreement without the other Party’s prior written consent. When
requesting such consent from the other Party, each Party shall submit all of the proposed
content of any such press release or public announcement at least ten days before its proposed
release.
	 
	12.4	 	Clause 12.3 shall not apply if and to the extent that such public announcement is required by:







	 	12.4.1	 	law; or
	 
	 	12.4.2	 	any securities exchange or regulatory or governmental body having jurisdiction over
it (including but not limited to the London Stock Exchange, the Panel on Takeovers and
Mergers and the Serious Fraud Office) and whether or not the requirement has the force
of law






	 	 	and provided that any such announcement shall be made only after consultation with the other
Party.




21









 






	12.5	 	Microscience may issue the press release set out in Part A of Schedule 6 upon Completion and
the Trust shall be permitted to use the statement set out in Part B of Schedule 6 in its
annual report, reviews and summaries of awards.





13. WARRANTIES AND INDEMNITY





	13.1	 	Each Party warrants to the other Party that:






	 	13.1.1	 	it has legal power, authority and right to enter into this Agreement and to perform
its respective obligations hereunder;
	 
	 	13.1.2	 	it is not at the Effective Date a party to any agreement, arrangement or
understanding with any third party which in any significant way prevents it from
fulfilling any of its material obligation hereunder;
	 
	 	13.1.3	 	this Agreement has been duly authorised, executed, and delivered by that Party and is
valid, binding, and legally enforceable obligation of that Party;
	 
	 	13.1.4	 	no consent, approval, authorisation, or order of any court or governmental agency or
body is required for the consummation of the transactions contemplated by this
Agreement (except that the manufacture, use, distribution and sale of Product will
require regulatory approval); and
	 
	 	13.1.5	 	the execution, delivery, and performance of this Agreement will not result in a
breach or violation of, or constitute a default under, any statute, regulation, or
other law or agreement or instrument to which it is a party or by which it is bound, or
any order, rule, or regulation of any court or governmental agency or body having
jurisdiction over it or any of its properties.






	13.2	 	Microscience and Microscience Limited represent and warrant to the Trust that:






	 	13.2.1	 	Microscience Limited is the sole legal and beneficial owner and, where registered,
the sole registered proprietor of all patent applications and patents set out in
Schedule 3 free from all Encumbrances, except as set out in Schedule 3;
	 
	 	13.2.2	 	Microscience Limited has the right to disclose the Background Know-How to the extent
required by Clause 10.15.1;
	 
	 	13.2.3	 	as far as they are aware, the Background Intellectual Property comprises all the
materially significant intellectual property rights required by the carrying on of the
Project as set out in this Agreement;
	 
	 	13.2.4	 	Microscience Limited is able to grant to the Trust the licences under the Background
Intellectual Property as set out in Clause 10;
	 
	 	13.2.5	 	as far as they are aware, the patent applications and patents set out in Schedule 3
are valid and enforceable and not subject to any pending or threatened claims,
challenges or proceedings;




22









 






	 	13.2.6	 	as far as they are aware, no third party has made unauthorised use of any
Background Intellectual Property, nor threatened to do so;
	 
	 	13.2.7	 	as far as they are aware, Microscience Limited has taken all steps and made all
payments which are required to prosecute, maintain and renew the patent applications
and patents set out in Schedule 3 within the required timescales; and
	 
	 	13.2.8	 	as far as they are aware, none of the activities of Microscience or Microscience
Limited relating to typhoid vaccines infringe, or have been alleged to infringe, the
intellectual property rights of any third party.






	13.3	 	Save as provided in this Clause 13, nothing in this Agreement shall be deemed to be, or
construed as, a representation or warranty by Microscience or Microscience Limited:






	 	13.3.1	 	as to the accuracy, safety, efficacy, or usefulness, for any purpose, of any matter
claimed in any of Microscience Limited’s Patent Rights which are Background
Intellectual Property;
	 
	 	13.3.2	 	that any patent will issue based upon any pending patent application included in the
Background Intellectual Property, or
	 
	 	13.3.3	 	that any patent included in the Background Intellectual Property which issues will be
valid.






	13.4	 	Subject to Clause 13.5, neither Party shall be liable to the other of any of the other
Party’s Affiliates, licensees or sublicensees for any of the following types of loss, damage,
cost or expense arising (whether in contract, tort, negligence, breach of statutory duty or
otherwise) under or in relation to this Agreement or the subject-matter of this Agreement:






	 	13.4.1	 	any loss of profits, business, contracts, anticipated savings, goodwill, or revenue;
	 
	 	13.4.2	 	any loss or corruption of data; or
	 
	 	13.4.3	 	any indirect or consequential loss or damage whatsoever,






	 	 	even if that Party was advised in advance of the possibility of such loss or damage.
	 
	13.5	 	Nothing in Clause 13.4 shall prohibit or hinder the exercise of either Party’s rights in
respect of any of the following matters, notwithstanding that any loss or damage that Party
may be seeking to recover is of the type referred to in Clause 13.4:






	 	13.5.1	 	death and personal injury caused by negligence of the other Party; and
	 
	 	13.5.2	 	any liability for fraud or fraudulent misrepresentation.






	13.6	 	Each Party shall be responsible for and indemnify and keep fully indemnified the other Party
and its Affiliates, officers, servant, agents, licensees and sublicensees (collectively the
“Indemnified Party”) against any and all liability, loss, damage, cost or expense




23









 






	 	 	(“Losses”) incurred or suffered by the Indemnified Party as a result of any claim by a third
party arising directly out of the research, development, marketing, sale, commercialisation
or distribution of the Product by, or on behalf of, that Party, except to the extent such
Losses result from the negligence or intentional misconduct of the Indemnified Party
(including, in particular, any act or omission by the Indemnified Party which is not in
accordance with the product release and characterization specifications referred to in
Clause 10.17).
	 
	13.7	 	Each Party shall maintain, at its sole cost, adequate general and product liability insurance
for such period as that Party continues to supply Product pursuant to this Agreement plus
three years, and shall ensure that the other Party’s interest is noted on the policy, if so
requested by the other Party. Each Party shall promptly, on request, supply the other Party
with a copy of each such policy of insurance.
	 
	13.8	 	Each Party shall promptly inform the other Party of, and deliver comprehensive written
details to the other Party of any safety or environmental concerns or issues reportable to, or
raised by, any Competent Authority which relate to the Product or other oral vaccine using
Microscience technology which might have an impact on the Product. Upon request of either
Party, the other Party shall use all reasonable endeavours to assist that Party in taking any
action with respect to the Product which is necessary or reasonably desirable as a consequence
of those safety or environmental concerns or issues.
	 
	13.9	 	In the event that either Party (the “First Party”) intends to seek indemnification under
Clause 13.6, it shall promptly inform the other Party (the “Second Party”) and the First Party
shall permit the Second Party and/or its insurers to direct and control the defence of the
claim, which shall use independent legal representation for the First Party where reasonably
necessary. The First Party shall provide such reasonable assistance as reasonably requested
by the Second Party (at the Second Party’s cost) in the defence of the claim, provided always
that nothing in this Clause 13.9 shall permit the First Party to make any admission on behalf
of the Second Party, or to settle any litigation without the prior written consent of, the
Second Party, which consent is not to be unreasonably withheld or delayed (except that the
Second Party may always withhold such consent on the instructions of its insurers).
	 
	13.10	 	The rights, powers and remedies provided in this Agreement are (except as expressly
provided) cumulative and not exclusive of any rights, powers and remedies provided by law, or
otherwise.





14. CONFIDENTIALITY





	14.1	 	The Trust undertakes and agrees not at any time, for any reason whatsoever, to disclose, or
permit to be disclosed, to any third party, or otherwise make use of, or permit use to be made
of (except as expressly permitted by this Agreement) any trade secrets or confidential
information relating, amongst other things, to:






	 	14.1.1	 	Microscience’s technology;
	 
	 	14.1.2	 	the business affairs or finances of Microscience; or




24









 






	 	14.1.3	 	the business affairs or finances of any Affiliate, licensee, sublicensee,
supplier, agent, distributor or customer of Microscience






	 	 	(“Confidential Information”) which comes into its possession pursuant to this Agreement.
	 
	14.2	 	This Clause 14 shall apply to the Background Intellectual Property and the Project
Intellectual Property on the basis that it is Confidential Information owned by Microscience
such that, except so far as is reasonably necessary for the Trust to exploit any Licence
granted to it in accordance with Clause 10, the Trust shall not disclose it without the
consent of Microscience, or otherwise than in accordance with the provisions of this Clause
14.
	 
	14.3	 	The Trust shall ensure that only those of its officers and employees and those of its
licensees, sublicensees, potential licensees or sublicensees and Affiliates who have a need to
know for the purposes of carrying out this Agreement are given access to Microscience’s
Confidential Information and that all such persons, prior to the disclosure of Confidential
Information to them, agree to be bound by the obligations of the Trust under this Clause 14.
The Trust shall enforce such obligations of all such persons.
	 
	14.4	 	The obligations of confidence referred to in this Clause 14 shall not extend to any
Confidential Information which:






	 	14.4.1	 	is at the time of disclosure, or thereafter becomes, generally available to the
public otherwise than by reason of a breach by the recipient of the provisions of this
Clause 14;
	 
	 	14.4.2	 	is known to the recipient without obligations of confidence prior to its receipt from
the disclosing Party, as can be shown by written record;
	 
	 	14.4.3	 	is subsequently disclosed to the recipient without obligations of confidence by
another party owing no such obligations in respect thereof;
	 
	 	14.4.4	 	is required to be disclosed by any applicable law or any Competent Authority to which
the recipient is from time to time subject; or
	 
	 	14.4.5	 	is independently developed by a person or persons with no access to the Confidential
Information disclosed by the disclosing Party, as demonstrated by written records,






	 	 	but the fact that an item is known to the public shall not be taken to preclude the
possibility that a compilation including the item, and/or a development relating to the
item, is not known to the public.
	 
	14.5	 	The obligations of the Trust (and all persons referred to in Clause 14.3) under this Clause
14 shall survive until ten years after the expiry or termination for whatever reason of this
Agreement.




25









 






	14.6	 	Each Party undertakes that, prior to any of its Affiliates ceasing to be an Affiliate, it
will procure that any such Affiliate that holds Confidential Information of the other Party
will give confidentiality and non-use undertakings to the other Party on terms no less
onerous than the terms of this Clause 14.





15. TERMS AND TERMINATION





	15.1	 	This Agreement shall come into effect on the Effective Date and, subject to earlier
termination in accordance with this Clause 15, shall continue in full force until the expiry
of all rights and obligations hereunder.
	 
	15.2	 	Either Party (“Terminating Party”) shall have the right to terminate this Agreement forthwith
at any time upon giving written notice of termination to the other Party (“Defaulting Party”),
upon the occurrence of any of the following events:






	 	15.2.1	 	the Defaulting Party commits a breach of a material obligation set out in this
Agreement which is not capable of remedy;
	 
	 	15.2.2	 	the Defaulting Party commits a breach of a material obligation set out in this
Agreement which is capable of remedy but has not been remedied within sixty (60) days
of the receipt by it of a notice from the other Party identifying the breach and
requiring its remedy;
	 
	 	15.2.3	 	the Defaulting Party becomes insolvent or any notice is issued for convening a
meeting at which a resolution is to be proposed or any petition is presented (which
notice or petition is not withdrawn or discharged within 14 days) for the winding up of
the Defaulting Party (other than voluntarily for the purpose of solvent amalgamation or
reconstruction), or an order is made or a resolution is passed for the winding up of
the Defaulting Party (other than voluntarily for the purpose of solvent amalgamation or
reconstruction);
	 
	 	15.2.4	 	any notice is given or petition presented or other step is taken in relation to the
appointment of an administrator, administrative receiver, receiver or liquidator in
respect of a material part of the Defaulting Party’s assets or business which is not
withdrawn or discharged within 14 days;
	 
	 	15.2.5	 	the Defaulting Party makes any composition with its creditors or takes or suffers any
similar or analogous action in consequence of debt;
	 
	 	15.2.6	 	a mortgagee, chargee or other encumbrancer takes possession of, any part of the
Defaulting Party’s assets or undertaking;
	 
	 	15.2.7	 	the Defaulting Party ceases to continue its business; or
	 
	 	15.2.8	 	the Defaulting Party becomes unable to pay its debts as and when they fall due.






	15.3	 	Microscience shall have the right to terminate this Agreement upon written notice to the
Trust in the event that Microscience decides that it would not be commercially viable to




26









 






	 	 	perform further work on the Project or to commercialise Product further or that there is a
technical issue precluding further progress of the Project.
	 
	15.4	 	Subject to Clause 15.5, if Microscience undergoes a Change of Control, the Trust shall have
the right to terminate this Agreement immediately if, in its reasonable opinion, the Change of
Control or its consequences would be incompatible with or have an adverse effect, on the
Trust’s charitable objectives.
	 
	15.5	 	At any time, Microscience may notify the Trust that a transaction is proposed that would
result in a Change of Control of Microscience. In the event that Microscience so notifies the
Trust, the Trust shall notify Microscience within 30 days of the date of receipt of such
notice if it will or will not terminate this Agreement following such Change of Control. In
the event that the Trust notifies Microscience that it will not terminate this Agreement
following such Change of Control or the Trust fails to respond to Microscience’s notice within
30 days of receipt, the Trust shall not be entitled to terminate this Agreement under Clause
15.4 following such Change of Control.





16. CONSEQUENCES OF TERMINATION





	16.1	 	Upon termination of this Agreement for whatever reason, Microscience shall return all funding
received from the Trust under this Agreement, which is unspent at the date of termination
(after deduction of costs and non-cancellable commitments incurred prior to the date of
termination).
	 
	16.2	 	In the event of termination of this Agreement by the Trust under Clause 15.2, or by
Microscience under clause 15.3:






	 	16.2.1	 	the Trust shall retain its rights under Clauses 6.1 and 6.2 and, for the avoidance of
doubt, Microscience’s corresponding obligations under those Sub-Clauses to pay
Royalties to the Trust shall continue;
	 
	 	16.2.2	 	Microscience shall retain its rights under Clause 6.3 and, for the avoidance of
doubt, the Trust’s corresponding obligation to pay a Royalty to Microscience under that
Sub-Clause shall continue;
	 
	 	16.2.3	 	the Trust’s rights and Microscience’s obligations under Clause 8 shall continue; and
	 
	 	16.2.4	 	each Party shall retain its rights under, and be subject to its obligations under, Clause 10.






	16.3	 	In the event of termination of this Agreement by Microscience under Clause 15.2:






	 	16.3.1	 	the Trust’s rights under Sub-Clauses 6.1 and 6.2 and under Clause 10 shall terminate; and




27









 






	 	16.3.2	 	the Trust’s rights and Microscience’s obligations under Clause 8 shall continue.






	16.4	 	In the event of termination of this Agreement by the Trust under Clause 15.4:






	 	16.4.1	 	the Trust’s rights under Sub-Clauses 6.1 and 6.2, and, for the avoidance of doubt,
Microscience’s corresponding obligations to pay Royalties under those Sub-Clauses,
shall be amended so that Microscience shall pay to the Trust amended Royalties
depending on the Instalments paid by the Trust as at the date of termination as
follows:





	 	 	 	 	 
	 

	 	Payment made
	 	Percentage of the Royalty set out in Clauses 6.1 and 6.2 which is payable
	 

	 	First Instalment
	 	[**]%
	 

	 	Second Instalment
	 	[**]%
	 

	 	Third Instalment
	 	[**]%







	 	16.4.2	 	the Trust’s rights and Microscience’s obligations under Clause 8 shall continue; and
	 
	 	16.4.3	 	the Trust’s rights under Clause 10 shall terminate.






	16.5	 	Termination or expiry of this Agreement for whatever reason shall not affect: (a) rights or
obligations which are expressed or intended to continue in force following termination or
expiry of this Agreement; or (b) the accrued rights of the Parties arising in any way out of
this Agreement as at the date of termination or expiry including in particular, but without
limitation, the right to recover damages and interest. Subject to the provisions of Clauses
16.2, 16.3 and 16.4, the provisions of Clauses 4 (Ownership of Project IP), 6 (Royalty), 7
(Books and Records), 8 (Equity Issue), 10 (Access to Product Throughout the World), 13
(Warranties and Indemnity), 14 (Confidentiality), 16 (Consequences of Termination), 22
(Dispute Resolution) and 26 (Third Party Rights) shall remain in full force and effect
following termination or expiry of this Agreement.





17. WAIVER





	17.1	 	Neither Party shall be deemed to have waived any of its rights or remedies conferred by this
Agreement unless the waiver is made in writing and signed by a duly authorised representative
of that Party. In particular, no delay or failure of either Party in exercising or enforcing
any of its rights or remedies conferred by this Agreement shall operate as a waiver of those
rights or remedies or so as to preclude or impair the exercise or enforcement of those rights
or remedies nor shall any partial exercise or enforcement of any right or remedy by either
Party preclude or impair any other exercise or enforcement of that right or remedy by that
Party.




28









 











18. ENTIRE AGREEMENT AND VARIATION





	18.1	 	This Agreement and the Application constitute the entire agreement and understanding between
the Parties and supersedes all prior oral or written understandings, arrangements,
representations or agreements between them relating to the subject matter of this Agreement
including, for the avoidance of doubt, the Letter of Intent between the Parties dated
3rd May 2004 and which became effective on 6th May 2004. No director,
employee or agent of either Party is authorised to make any representation or warranty to
another party not contained in this Agreement, and each Party acknowledges that it has not
relied on any such oral or written representations or warranties provided always that nothing
in this Clause 18.1 shall operate to limit or exclude either Party’s liability for fraud or
fraudulent misrepresentation.
	 
	18.2	 	No variation, amendments, modification or supplement to this Agreement shall be valid unless
made in writing and signed by a duly authorised representative of each Party.





19. NOTICES





	19.1	 	Any notice to be given pursuant to this Agreement shall be in writing and shall be delivered
by hand, sent by registered or recorded delivery, airmail post or sent by facsimile confirmed
by registered or recorded delivery post to the address or facsimile number of the recipient
Party set out below or such other address or facsimile number as a Party may from time to time
designate by written notice to the other Party:
	 
	 	 	Address of the Trust:
	 
	 	 	215 Euston Road, London NW1 2BE
	 
	 	 	Fax Number: +44 (0)207 611 8857
	 
	 	 	All notices to be marked for the attention of the Head of Business Development, cc The
Awards Officer, Technology Transfer Division.
	 
	 	 	Address of Microscience:
	 
	 	 	540-545 Eskdale Road, Winnersh Triangle, Wokingham, Berkshire, RG41 5TU
	 
	 	 	Fax Number: +44 (0)118 944 3301
	 
	 	 	All notices to be marked for the attention of Rod Richards, Chief Executive Officer.
	 
	19.2	 	Any notice given pursuant to this Clause 19 shall be deemed to have been received:-






	 	19.2.1	 	in the case of delivery by hand, when delivered; or




29









 






	 	19.2.2	 	in the case of sending by post:






	 	19.2.2.1	 	where posted in the country of the addressee, on the third Business Day
following the day of posting; and
	 
	 	19.2.2.2	 	where posted in any other country, on the seventh Business Day
following the day of posting; or






	 	19.2.3	 	in the case of facsimile, on acknowledgement by the recipient facsimile receiving
equipment on a Business Day if the acknowledgement occurs before 1700 hours local time
of the recipient and in any other case on the following Business Day.





20. ASSIGNMENT





	20.1	 	Neither Party shall, assign, charge or declare a trust over the benefit and/or burden of this
Agreement, except to the extent that the same occurs as a result of the Encumbrances referred
to in Schedule 3.





21. FORCE MAJEURE





	21.1	 	If either Party is unable to carry out any of its obligations under this Agreement due to
Force Majeure, this Agreement shall remain in effect but the relevant obligations of the Party
unable to carry out its obligations under this Agreement shall be suspended for a period equal
to the duration of the circumstances of Force Majeure, provided that:






	 	21.1.1	 	the suspension of performance is of no greater scope than is required by the Force
Majeure;
	 
	 	21.1.2	 	the Party unable to carry out its obligations under this Agreement gives the other
Party prompt notice of the circumstance of Force Majeure, including the nature of the
occurrence and its expected duration, and continues to furnish regular reports during
the period of Force Majeure;
	 
	 	21.1.3	 	the Party unable to carry out its obligations under this Agreement uses all
reasonable efforts to remedy its inability to perform and to mitigate the effects of
the circumstances of Force Majeure; and
	 
	 	21.1.4	 	as soon as practicable after the event which constitutes Force Majeure, the Parties
shall discuss how best to continue their operations as far as possible in accordance
with this Agreement.






	21.2	 	If Force Majeure is continuing at the expiry of six (6) months from its first occurrence, the
Parties shall enter into bona fide discussions with a view to alleviating its effects, or to
agreeing upon such alternative arrangements as may be fair and reasonable.




30









 











22. DISPUTE RESOLUTION





	22.1	 	Any question, difference or dispute which may arise concerning the construction meaning or
effect of this Agreement or concerning the rights and liabilities of the Parties hereunder or
any other matter arising out of or in connection with this Agreement shall first be submitted
to the Director of the Technology Transfer Division of the Trust and Rod Richards, Chief
Executive Officer of Microscience for resolution, who may call on others to advise them as
they see fit.
	 
	22.2	 	If the Director of the Technology Transfer Division of the Trust and the Chief Executive
Officer of Microscience fail to resolve the dispute within 28 days, such dispute shall be
referred to and finally resolved by arbitration in accordance with the Rules of Arbitration of
the International Chamber of Commerce by one arbitrator appointed in accordance with those
Rules. This Agreement shall be governed by the laws of England and Wales, the arbitration
shall have its seat in London and the language to be used in the arbitration shall be English.





23. SEVERANCE OF TERMS





	23.1	 	If the whole or any part of this Agreement is or becomes, or is declared illegal, invalid or
unenforceable in any jurisdiction for any reason (including both by reason of the provisions
of any legislation and also by reason of any court or Competent Authority which either has
jurisdiction over this Agreement or has jurisdiction over any of the Parties):






	 	23.1.1	 	in the case of the illegality, invalidity or unenforceability of the whole of this
Agreement, it shall terminate only in relation to the jurisdiction in question; or
	 
	 	23.1.2	 	in the case of the illegality, invalidity or unenforceability of part of this
Agreement, that part shall be severed from this Agreement in the jurisdiction in
question and that illegality, invalidity or unenforceability shall not in any way
whatsoever prejudice or affect the remaining parts of this Agreement, which shall
continue in full force and effect.






	23.2	 	If, in the reasonable opinion of either Party, any severance under this Clause 23 materially
affects the commercial basis of this Agreement, the Parties shall discuss, in good faith, ways
to eliminate the material effect.





24. NO PARTNERSHIP





	24.1	 	None of the provisions of this Agreement shall be deemed to constitute a partnership between
the Parties and neither Party shall have any authority to bind the other in any way except as
provided in this Agreement.





25. COSTS AND EXECUTION





	25.1	 	Each Party shall bear its own legal costs, legal fees and other expenses incurred in the
preparation and execution of this Agreement.




31









 






	25.2	 	Each Party shall, at its own cost and expense, carry out, or use all reasonable endeavours
to ensure the carrying out of, whatever further actions (including the execution of further
documents) the other Party reasonably requires from time to time for the purpose of giving
that other Party the full benefit of the provisions of this Agreement both during and after
the term of this Agreement.





26. THIRD PARTY RIGHTS





	26.1	 	This Agreement is not intended by the Parties to create rights or benefits in favour of any
person not party to this Agreement, or make any rights or benefits enforceable by, or on
behalf of, such third parties. For the avoidance of doubt, all laws providing to the contrary
in any country including the relevant provisions of the Contracts (Rights of Third Parties)
Act 1999 in the United Kingdom are hereby excluded to the fullest extent permitted.





This Agreement shall come into force on the date given at the beginning of this Agreement.



	 	 	 	 	 	 	 	 	 
	Signed for and on behalf of

	 	 	)	 	 	 	 	 
	THE WELLCOME TRUST

	 	 	)	 	 	 	 	 
	LIMITED as trustee of

	 	 	)	 	 	 	 	 
	The Wellcome Trust

	 	 	)	 	 	/s/ [Illegible]
 
 

	 	 
	by its authorised signatory

	 	 	)	 	 	Authorised Signatory	 	 
	 
	 	 	 	 	 	 	 	 
	Signed for and on behalf of

	 	 	)	 	 	 	 	 
	THE WELLCOME TRUST

	 	 	)	 	 	 	 	 
	LIMITED as trustee of

	 	 	)	 	 	 	 	 
	The Wellcome Trust

	 	 	)	 	 	/s/ [Illegible]
 
 

	 	 
	by its authorised signatory

	 	 	)	 	 	Authorised Signatory	 	 
	 
	 	 	 	 	 	 	 	 
	Signed for and on behalf of

	 	 	)	 	 	 	 	 
	MICROSCIENCE

	 	 	)	 	 	/s/ [Illegible]
 
 

	 	 
	HOLDINGS PLC

	 	 	)	 	 	Director	 	 






32









 






	 	 	 	 	 	 	 	 	 
	Signed for and on behalf of

	 	 	)	 	 	/s/ R. Richards
 
 

	 	 
	MICROSCIENCE

	 	 	)	 	 	Chief Executive	 	 
	LIMITED

	 	 	)	 	 	Director	 	 






33









 






Schedule 1




The Project




The Trust shall pay the following amounts to Microscience upon the achievement of the following
Project Milestones:



	 	 	 	 	 	 	 
	Project Milestone	 	Project Milestone Criteria	 	Project Milestone Date	 	Instalment
	Completion

	 	Signature of this agreement
	 	[**]
	 	£[**]
	 
	 	 	 	 	 	 
	Preparation,
conduct and
completion of Phase
II Adult Study in
Vietnam as set out
in the Application

	 	Completion of ID steps
0-15, as described in
Schedule 2 under the
heading “Revised Gantt
chart”
	 	[**]
	 	£[**]
	 
	 	 	 	 	 	 
	Decision to
initiate the phase
III surveillance
based on commercial
partnering/NGO
funding

	 	Letter to the Trust signed
by Microscience’s CEO and
chairman of the board, or
their equivalent
positions, setting out the
key terms on which funding
will be made available for
the phase III study
	 	[**]
	 	£[**]






Instalments of Programme Related Investment payable upon achievement of each Project Milestone on
or before the relevant Project Milestone Date.



34









 








Schedule 2

Documents relating to the performance of the Project




2.1 Microscience’s Application for a Strategic Translation Award dated [ ]


Application for a Strategic Translation Award




Please return this form and six copies (unfolded) to:




Technology Transfer



The Wellcome Trust



183 Euston Road



London NW1 2BE



Tel: 020 7611 8202



Fax: 020 7611 8857



E-mail: techtransfer@wellcome.ac.uk



Web: www.wellcome.ac.uk/techtransfer



The Wellcome Trust is a charity whose
mission is to foster and promote research
with the aim of improving human and animal
health (registered charity no. 210183). Its
able Trustee is The Wellcome Trust Limited, a
company registered in England, no. 27711030,
whose registered office is 183 Euston Road,
London NW1 2BE.



TA-2211 [Illegible]



The Wellcome Trust




35









 








USE OF YOUR INFORMATION




The Wellcome Trust is committed to protecting the privacy of your personal information. Information
that you supply in connection with this application and any funding arising from it will be treated
in confidence, used for processing and evaluating your application, and will be stored by the
Wellcome Trust, its agents and/or advisors in accordance with the Data Protection Act 1998. It may
also be disclosed to external peer reviewers, some of whom may be based outside of the EU. The
Wellcome Trust may publish basic details of successful awards,
e.g. on its website or in its Annual Report, and contact you for your views on its funding schemes
and application processes. Please contact the Wellcome Trust if you have any further questions
about its
policy
on data protection.



The Wellcome Trust would like to be able to contact you to let you know about new award schemes and
initiatives that may be of interest to you. If you would prefer not to be contacted about these,
please check this box. o



Q1 Principal applicant:




	 	 	 
	Surname:

	 	[**]
	 
	 	 
	Forename

	 	[**]
	 
	 	 
	Title:

	 	[**]
	 
	 	 
	Position:

	 	[**]
	 
	 	 
	Employing Organization:

	 	               Microscience Ltd






Q2 Title of project (no more than 220 characters):









The safety and immunogenicity of a single dose oral typhoid
vaccine in Vietnamese healthy adults and children and
identification and preparation of a field site for a Phase III
efficacy study







	 	 	 
	Q3 Period for which support is sought (state in months):

	 	24 months
	 
	 	 
	Q4 Proposed start date (dd/mm/yy):

	 	01/10/04
	 
	 	 
	Q5 Does the proposal arise from previous Wellcome Trust funding?

	 	      o Yes þ No
	 
	 	 
	Q6 Total requested cost (*deleted as appropriate):

	 	£1,410,788
	 
	 	 
	               Cumulative cost to Objective 1:

	 	£222,061
	 
	 	 
	               Cumulative cost to Objective 2*:

	 	£1,290,576
	 
	 	 
	               Cumulative cost to Objective 3*:

	 	£1,410,788






36









 






	 	 	 
	Principal applicant:

	 	[**]
	 
	 	 
	Project title:

	 	The safety and immunogenicity of a single dose oral typhoid vaccine in Vietnamese healthy adults and children and
identification
and preparation of a field site for a Phase III efficacy study






Undertakings





	(I)	 	In signing the application form where shown below, and in consideration of the receipt of
this application by the Wellcome Trust, all applicants (principal applicant, coapplicant,
sponsors, technology transfer office/group representatives) UNDERTAKE that the information
provided in the application form and otherwise in connection with this application is to the
best of their knowledge and belief accurate and complete and that, in relation to any award of
grant resulting from the application, they will:






	 	1.	 	Take all reasonable actions to ensure that the Wellcome Trust’s contribution to the
funding of the research is suitably acknowledged.
	 
	 	2.	 	If research papers (whether based wholly or partly upon the research to be funded by
the grant) are published, forward copies to the Wellcome Trust upon publication.
	 
	 	3.	 	Comply as Wellcome Trust-funded researchers with the Wellcome Trust’s principles and
policies on relationships between Wellcome Trust-funded researchers and commercial entities
as set out in Annex A to the Wellcome Trust’s grant conditions.
	 
	 	4.	 	Meet the requirements of the Wellcome Trust, as set out in the grant conditions, prior
to entering into an arrangement with any enterprise that will provide for the exploitation
of any results arising from any activity funded under a Wellcome Trust award.
	 
	 	5.	 	Promptly inform the Wellcome Trust of any material changes during the period of the
grant to any of the details provided in this application.





I have read the conditions under which grants are awarded and the undertakings detailed above and,
if a grant is made, I agree to abide by them. I shall be actively engaged in the day-to-day
control of the project. I consent to the information provided in this application being used and
disclosed in accordance with the principles set out in the Wellcome Trust Data Protection statement
which appears on this form.



	 	 	 	 	 	 	 	 	 
	Signature of applicant

	 	N/A
	 	Date:
	 	 
 

	 	 
	 
	 	 	 	 	 	 	 	 
	Signature of technology transfer office/group
joint applicant

	 	 
 

	 	Date:
	 	 
 

	 	 
	 
	 	 	 	 	 	 	 	 
	Signature of coapplicant

	 	N/A
	 	Date:
	 	 
 

	 	 
	 
	 	 	 	 	 	 	 	 
	Signature of sponsor (if applicable)

	 	 
 

	 	Date:
	 	 
 

	 	 







	(II)	 	In signing the application form where shown below, and in consideration of the receipt of
this application by the Wellcome Trust, the Head of the Department and Head of Technology
Transfer Office/Group UNDERTAKE that the information provided in the application form and
otherwise in connection with this application is to the best of his/her knowledge and belief
accurate and complete and that, in relation to any award of grant resulting from the
application, he/she will:






	 	1.	 	Ensure compliance with the Wellcome Trust’s principles and policies on relationships
between Wellcome Trust-funded researchers and commercial entities as set out in Annex A to
the Wellcome Trust’s grant conditions.
	 
	 	2.	 	Meet the requirements of the Wellcome Trust, as set out in the grant conditions, prior
to entering into an arrangement with any enterprise that will provide for the exploitation
of any results arising from any activity funded under a Wellcome Trust award.
	 
	 	3.	 	Promptly inform the Wellcome Trust of any material changes during the period of the
grant to any of the details provided in this application.





I have read the conditions under which grants are awarded and the undertakings detained above and,
if a grant is made, I agree to abide by them. I confirm that I have read and support this
application, that I agree to this research being carried out in my department, and that all
necessary licences and approvals have been or are being obtained.



	 	 	 	 	 	 	 
	Signature of Head of Department                 N/A

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37









 








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38









 








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39









 






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40









 






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41









 






Q7 Summaries of University Translation Award research and commercialization objectives




(Both parts combined should be no more than 400 words.)



(a) For technically qualified assessors:








A breakthrough has been made in the development of an improved oral typhoid vaccine
through the application of functional genomics sciences. This has led to the
identification of several genes in Salmonella species that are essential for virulence
providing new gene targets for attenuation, resulting in the development of a novel live
attenuated typhoid vaccine that can be administered orally and is safe and immunogenic at
a single dose.



The live attenuated Salmonella typhi strain S. typhi (Ty2 aroC ̄ssaV ̄) ZH9 contains defined
(independently attenuating) non-reverting deletions in two genes,
aroC and ssaV. The ssaV
gene is encoded on SPI-2, Salmonella Pathogenicity Island 2. SPI-2 encodes a type III
secretion system and ssaV encodes a structural component of the secretory apparatus. SPI-2
is required for growth and survival within macrophages, one of the mechanisms by which S.
typhi is spread systemically. Therefore, a mutation in this gene will prevent systemic
spread of the vaccine strain, an important safety consideration for live vaccines.



The vaccine has been tested in clinical studies involving over 100 US and UK subjects and
has shown to have an excellent safety profile (no bacteraemias or persistent shedding
detected) and after a single dose, stimulates strong mucosal and systemic immune responses
comparable to those stimulated by four doses of the currently licensed vaccine.



A single dose vaccine that does not require a needle for administration would bring
enormous healthcare benefits to developing countries where typhoid is endemic and it is
difficult to maintain the cold chain. The vaccine offers a new opportunity for the control
and possibly the future eradication of typhoid from the wild.



The objectives of the project are to clinically evaluate the vaccine in healthy Vietnamese
adults and children in Phase II studies and to set up a field site in preparation for
efficacy testing. The project will be carried out in collaboration with the Oxford
University Wellcome Trust Unit in Viet Nam, [**] bringing together considerable expertise
in vaccinology and specifically on the development of typhoid vaccines.



The
STA is critical to the eventual commercialisation of the product in
any territory. The commercial market for typhoid vaccines is not
large and it is difficult for Microscience to justify funding the
whole programme required to gain approval of the product, either as a
traveller’s vaccine, or in developing countries, given that the
Company has a number of more commercially attractive vaccines in the
portfolio.



However, Microscience recognises the importance of this vaccine in providing substantial
healthcare benefits in the developing world and would like to ensure that if the vaccine
is successful, those benefits are delivered.



The route to commercialisation of the vaccine whether it is for travellers or the
developing world will involve carrying out a large efficacy study in a country where
typhoid is endemic. The STA proposal is critical for taking the first steps in this
process and addressing one of the key technical barriers relating to transfer of vaccines
from the developed to the developing world, that is whether the safety and immunogenicity
profiles will be similar, particularly in children who will form the bulk of the cohort in
the efficacy study. It will be difficult to obtain further investment into the project
until this key question has been answered. It is also essential, in parallel to the
clinical studies, to establish a field site than can subsequently be used for the efficacy
study. Establishing the incidence rate for typhoid will allow detail planning of the
efficacy study, particularly in terms of the numbers of subjects that will need to be
involved giving an accurate view of what future funding will be required for the efficacy
study which will be pivotal for gaining approval of the product.



If the vaccine proves to be successful in the stepping stone studies and in the
establishment of the field site in Viet Nam it should provide leverage for obtaining
additional funding, either from commercial or NGO sources.







(b) For lay readers:



42









 













Typhoid fever remains a major disease of the developing world. The spread of bacteria
that are resistant to all affordable antibiotics raises the possibility of untreatable
typhoid fever and a return to the pre-antibiotic era when 30% of patients died. There is
no currently available affordable vaccine that offers long term protection after a single
dose. The application of genomic sciences has resulted in a breakthrough in the
development of an improved typhoid vaccine that can be given orally and is effective at a
single dose. The vaccine has been tested in studies involving over 100 subjects in the US
and UK and has shown to have an excellent safety profile and after a single dose,
stimulates the body to make immune responses equivalent to those stimulated by four doses
of the currently licensed vaccine. A single dose vaccine that does not require a needle
for administration would bring enormous healthcare benefits to developing
countries where typhoid is endemic and it is difficult to maintain the cold chain.
The vaccine offers a new opportunity for the control and possibly the future eradication
of typhoid from the wild. The objectives of the project are to clinically evaluate the
vaccine in healthy Vietnamese adults and children and to identify and set up a field site
in Viet Nam where a future study can be carried out to assess whether it can protect
against typhoid fever.



The STA is critical to the eventual commercialisation of the product in any territory. The commercial market for typhoid vaccines is not
large and it is difficult for Microscience to justify funding the
whole programme required to gain approval of the product, either as a
traveller’s vaccine, or in developing countries, given that the
Company has a number of more commercially attractive vaccines in the
portfolio.



However, Microscience recognises the importance of this vaccine in providing substantial
healthcare benefits in the developing world and would like to ensure that if the vaccine
is successful, those benefits are delivered.



The route to commercialisation of the vaccine whether it is for travellers or the
developing world will involve carrying out a large efficacy study in a country where
typhoid is endemic. The STA proposal is critical for taking the first steps in this
process and addressing one of the key technical barriers relating to transfer of
vaccines from the developed to the developing world, that is whether the safety and
immunogenicity profiles will be similar, particularly in children who will form the bulk
of the cohort in the efficacy study. It will be difficult to obtain further investment
into the project until this key question has been answered. It is also essential, in
parallel to the clinical studies, to establish a field site that can subsequently be used
for the efficacy study. Establishing the incidence rate for typhoid will allow detail
planning of the efficacy study, particularly in terms of the numbers of subjects that will
need to be involved, giving an accurate view of what future funding will be required for
the efficacy study which will be pivotal for gaining approval of the product.



If the vaccine proves to be successful in the stepping stone studies and in the
establishment of the field site in Viet Nam it should provide leverage for obtaining
additional funding, either from commercial or NGO sources.







Q8. How did you hear about this award scheme?




	 	 	 	 	 
	Wellcome Trust

website o

	 	Other Wellcome Trust

contact o
	 	University or technology transfer

office/group  þ 






	 	 	 	 	 
	Press o Other (please
specify) 
	 






43









 






Q9 Previous applications to the Wellcome Trust




þ Yes o No





	(a)	 	Is this the principal applicant’s first application to the Wellcome Trust?
	 
	 	 	If no, please give details of previous approaches over the last five years.
	 
	 	 	Indicate with an (*) those awards (if any) which have contributed to the background of this
proposal.










N/A








	(b)	 	Is this application a resubmission of an application previously considered by the                 o Yes þ No





	 	 	 	 	 
	 

	 	Wellcome Trust?	 	 
	 
	 	 	 	 
	 

	 	If yes, when and where was it considered?
	 	N/A
	 
	 	 	 	 
	 

	 	Please give the Wellcome Trust’s reference number:
	 	N/A
	 
	 	 	 	 
	 	 	In a covering letter briefly state how this application differs from the original.






44









 






Q10 Details of other sources of funding





	 	 	State name of awarding body, title of project, amount awarded, dates of support and
proportion of time spent on each project.
	 
	(a)	 	Current sources of funding
	 
	 	 	Indicate with an (*) those awards (if any) which have contributed to the background of this
proposal.










To date the only source of funding has been through Microscience Ltd, a
privately owned UK company working on the development of novel vaccines and
immunotherapeutics for prevention and treatment of infectious disease. The
Company was founded on vaccine technology developed at Imperial College and was
spun out in 1997. To date the Company has raised £[**] in the form of private
equity investment. The major investors are Merlin, Apax Partners, Advent
Venture Partners and J.P. Morgan Partners. The funding has enabled Microscience
to develop five vaccine products, including the oral typhoid vaccine, all of
which are now undergoing clinical testing in the U.K. and U.S.

To date approximately £[**] has been spent by Microscience on the development
of the oral typhoid vaccine over the past five years. It is estimated that
approximately £[**] is still required to complete all the activities required
to commercialise the product.







	(b)	 	Any other source of funding that has directly contributed to the background of this proposal.










No







45









 






			
	Name of applicant:	 	[**]





	 	 	 	 	 	 	 
	Q11	 	Patent Information
	 
	 	 	 	 	 	 
	 	 	(Please continue on an additional sheet if necessary.)
	 
	 	 	 	 	 	 
	 	 	Have any patent(s) or patent application(s) been filed by the applicant(s)                                              þ Yes o No
	 	 	which relate to this proposal?
	 
	 	 	 	 	 	 
	 	 	If yes, please provide details:
	 
	 	 	 	 	 	 
	 

	 	 1)
	 	Application number or
publication number:
	 	W096/17951
	 
	 	 	 	 	 	 
	 

	 	 	 	Priority date:
	 	11 December 1995
	 
	 	 	 	 	 	 
	 

	 	 	 	Inventors:
	 	D W Holden, J E Shea, M Hensel
	 
	 	 	 	 	 	 
	 

	 	 	 	Applicant:
	 	RPMS (now co-owned by Microscience Ltd)
	 
	 	 	 	 	 	 
	 

	 	 	 	Funding source:
	 	N/A
	 
	 	 	 	 	 	 
	 

	 	 2)
	 	Application number
or publication
number:
	 	W000/68261
	 
	 	 	 	 	 	 
	 

	 	 	 	Priority date:
	 	10 May 1999
	 
	 	 	 	 	 	 
	 

	 	 	 	Inventors:
	 	G Dougan, J D Santengelo, D W Holden, J E Shea, Z Hindle
	 
	 	 	 	 	 	 
	 

	 	 	 	Applicant:
	 	Microscience Ltd
	 
	 	 	 	 	 	 
	 

	 	 	 	Funding source:
	 	N/A






How do these patent(s) or patent application(s) relate to this proposal?








The typhoid vaccine candidate contains mutations in aroC and ssaV.



W096/17951
— Contains claims to use of strains harbouring mutations in
Salmonella Pathogenicity Island 2, including the ssaV gene.



W000/68261 — Claims to the combination of aroC and ssaV. Claim for the
combination being particularly useful for making attenuated mutants of
Salmonellae.







46









 





Q12 Details of the investigation





	 	 	Please refer to the guidelines notes before completing this section.
	 
	(a)	 	Please detail the key objectives of the proposal, relating these to the proposed project
Objectives.










The overall objective of the proposal is to translate the Phase I/II clinical
findings from an improved oral typhoid vaccine being developed in the UK and US, to a
country where typhoid is endemic, in order to prepare for a large field study in which the
vaccine can be evaluated for efficacy. This will be achieved by carrying out a Phase II
programme in Viet Nam in healthy adult subjects and school age children in order to
confirm the safety and immunogenicity of the vaccine in a Vietnamese population, providing
assurance that the vaccine is suitable for use in a large efficacy study in the Mekong
Delta of Viet Nam. The proposal will address one of the key technical barriers associated
with transfer of vaccines from developed to developing countries; the vaccine has so far
been tested in healthy subjects in countries where typhoid is not endemic, but it is known
that the safety and immunogenicity profiles of vaccines, particularly live vaccines given
orally, can be different in subjects where the disease is endemic and where the
socio-economic conditions are very different. The proposed project will therefore
highlight any differences between the different populations and will provide new
scientific data on this issue that will be useful for the development of other vaccines.



The other major objective will be to identify and prepare a site in the Mekong Delta where
a large field study can be performed to establish the efficacy of the vaccine. The site
development will be carried out in parallel to the Phase II programme described above.



In order to achieve the overall objective the key objectives of the project are as follows:



Initiation of a Phase II programme in Viet Nam in healthy adult volunteers and children:




	 	•	 	Identification of site
	 
	 	•	 	Clinical protocol development
	 
	 	•	 	Regulatory approval from Vietnamese and US authorities
	 
	 	•	 	Assay transfer
	 
	 	•	 	Manufacture and release of clinical material
	 
	 	•	 	Screening and recruitment of subjects





Demonstration of safety, tolerability and immunogenicity in Vietnamese adults and children





	 	•	 	Dosing
	 
	 	•	 	Monitoring of study (safety and GCP)
	 
	 	•	 	Evaluation of safety
	 
	 	•	 	Completion of immunoassays
	 
	 	•	 	Management and validation of data





Preparation of field site for Phase III study





	 	•	 	Identification of site
	 
	 	•	 	Establishment of infrastructure
	 
	 	•	 	Perform Census
	 
	 	•	 	Establishment and provide training in diagnostic tools
	 
	 	•	 	Disease surveillance









47









 






			
	Name of applicant:	 	[**]






	(b)	 	Describe how this proposal will ultimately lead to healthcare benefit










The proposal could lead to considerable healthcare benefits for both the
developing and developed world. The activities outlined in the proposal are
the first steps in a clinical evaluation of the vaccine critical for moving to
an efficacy study in an endemic area. Such a study will be required for
approval of the vaccine in any country since there are no accepted correlates
of immunity. All other typhoid vaccines have been approved on efficacy data
generated in endemic areas. Typhoid fever remains a very significant global
health problem with an estimated 17 to 33 million cases occurring worldwide
annually resulting in 600,000 deaths, virtually all these cases occur in the
developing world. In the last few years there has been the worrying
development and global spread of bacteria that are resistant to all affordable
antibiotics. Over 90% of isolates in Southern Viet Nam are resistant to all
first line antibiotics making the need for an effective and affordable vaccine
more urgent. There are licensed vaccines available to prevent typhoid fever
but these are less than ideal for control of typhoid fever in developing
countries. The currently licensed oral typhoid vaccine achieves protection in
60-70% of recipients but requires four doses resulting in compliance issues and
difficulty in maintaining the cold chain. The single dose injectable vaccine
based on the surface polysaccharide Vi is also not ideal as it’s administration
requires the use of needles and being a polysaccharride, it is poorly
immunogenic in young children. The incidence of typhoid fever is highest in
school age and pre-school age children in developing countries.



A single dose vaccine that is immunogenic in young children and does not
require a needle for administration would therefore bring enormous healthcare
benefits to developing countries where it is difficult to maintain the cold
chain that is required for multi-dose vaccines. Furthermore, because S. typhi
is a human restricted pathogen, has no animal reservoirs and does not persist
in the environment, the vaccine also offers a new opportunity for the control
and possibly the future eradication of typhoid from the wild.



Additional healthcare benefits will be derived from setting up of a field site
for testing efficacy. Establishing the infrastructure and expertise at a
potential field site will also provide information on the general disease
burden of the population making it possible to derive other healthcare
strategies to address other disease targets.



Finally, the proposal could also lead to the approval of the vaccine for the
prevention of typhoid fever in travelers to endemic areas.







48









 






	(c)	 	Give relevant technical background information (maximum 11/2 pages)










Modern molecular biology techniques and increasing knowledge of Salmonella
pathogenesis have led to the identification of several genes that are essential
for in vivo growth and survival of these organisms. (1) This has provided new
gene targets for attenuation, leading to the concept that future live vaccine
strains can be rationally attenuated by introducing defined mutations into
selected genes that are known to be involved in virulence. This will
facilitate the development of improved vaccines, particularly in terms of the
immunogenicity and therefore the number of doses that have to be given.



Microscience has constructed a Salmonella typhi vaccine strain S. typhi (Ty2
aroC ̄ssaV ̄) ZH9 that contains defined (independently attenuating) deletions in
two genes, aroC and ssaV. (2) The aroC gene encodes chorismate synthase, an
enzyme involved in the biosynthesis of aromatic compounds. Aro mutations are
well described as being attenuating for Salmonella in humans, (2) and the basis
is presumed to be that two aromatic compounds, para-aminobenzoic acid and
2,3-dihydroxyaminobenzoic acid are limiting for growth in mammalian tissue.
The ssaV gene is encoded on SPI-2, Salmonella Pathogenicity Island 2, SPI-2
encodes a type III secretion system and ssaV is believed to encode a structural
component of the secretory apparatus. SPI-2 mutations have previously been
shown to be attenuating in mice, (3) and there is evidence that this is because
SPI-2 is required for growth within macrophages, the mechanism by which S.
typhi is thought to be spread systemically. Therefore, a mutation in this gene
will prevent systemic spread of the vaccine strain.



S. typhi (Ty2 aroC ̄ ssaV ̄) ZH9 is derived from the virulent S. typhi strain
Ty2. This strain has been used as a background strain for constructing
candidate typhoid vaccines previously evaluated in volunteers. The currently
licensed live Salmonella vaccine is derived from this strain.



S. typhi (Ty2 aroC ̄ ssaV ̄) ZH9 is being developed as a single dose, orally
delivered vaccine that will protect against typhoid fever. (4)



The attenuation of S. typhi (Ty2 aroC ̄ ssaV ̄) ZH9 has been demonstrated
directly by comparing the replication of S. typhi (Ty2 aroC ̄ ssaV ̄) ZH9 with S.
typhi (Ty2 aroC ̄) DTY8, which harbours a single aro mutation, in human
macrophage-like cells in the presence and absence of aromatic compound
supplements. S. typhi (Ty2 aroC ̄ ssaV ̄) ZH9 was highly attenuated for growth
in macrophages since it failed to replicate and bacterial killing was observed,
even in the presence of aromatic compounds. (5) This is an important finding,
demonstrating the utility of mutations in SPI-2 as an attenuation strategy for
Salmonella. This adds an additional level of safety to the strain.



The attenuation of vaccine strain S. typhi (Ty2 aroC ̄ ssaV ̄) ZH9 has also been
demonstrated indirectly by comparing the attenuation of Salmonella typhimurium
(S. typhimurium) strains harboring similar mutations in mice. S. typhi does
not infect mice. However, genetically-susceptible mice infected with S.
typhimurium develop a systemic “typhoid-like” disease and this mouse typhoid
model has been used to predict the usefulness of attenuating mutations in S.
typhi. This model has been used to demonstrate a safety advantage of a
mutation in SPI-2 (such as ssaV) in combination with an aro mutation, over that
of an aro mutation alone. (5)



Both IFN-y and IL-12 are required for control of Salmonella infection in mouse
and man, therefore, mice deficient in either IL-12 or IFN-y are useful models
of immunocompromised humans. The attenuation of a SPI-2 (ssaJ) transposon
insertion mutant and an aro (aroA) transposon insertion mutant of S.
typhimurium were compared in both IFN-y KO mice and in mice treated wit
h IL-12
specific antibodies. No clinical symptoms of disease were observed with the
SPI-2 mutant in either class of immunocompromised mouse and clearance from the
tissues was observed. In contrast, the aro mutant replicated to high levels in
the tissues and caused death of both the IFN- KO and anti-IL 12-treated mice.
Further studies sought to assess the attenuation of S. typhimurium harboring
defined deletions in aroC and ssaV identical to those present in S. typhi (Ty2
aroC ̄ ssaV ̄) ZH9. The aroC ssaV double mutant strain S. typhimurium (TML aroC ̄
ssaV ̄) WTO5 was completely attenuated in IFN — KO mice (100% survival) whereas
the single aroC mutant caused up to 100% mortality. (5) Further studies in
conventional mice showed that the aroC ssaV double mutant colonized the mouse
tissues at lower levels than a single aroC mutant and was cleared more rapidly
from the tissues. These data generated in the mouse typhoid model further
demonstrate the utility of mutations in SPI-2 in combination with an aro
mutation as an attenuation strategy for Salmonella and provide confidence that
S. typhi (Ty2 aroC ̄ ssaV ̄) ZH9 will be highly attenuated in humans with an
increased attenuation over single aro mutants.







49









 










Give relevant technical background information (continued)



To date S. typhi (Ty2 aroC ̄ ssaV ̄) ZH9 has been administered to over 80 healthy
adult volunteers in three studies. Full details and results of these studies
are provided in Appendix A in the form of a published paper and two clinical
trial study reports. A summary of the design of the studies and results is
provided below:



In the first study (Study MS01.01) 9 subjects (3 per cohort) received doses of
either 107, 108 or 109 CFU of a frozen
formulation of the vaccine. (4) In the second study (Study MS01.03) 48 subjects
(16 per cohort) received doses of 5 x 107, 5 x 108 or 5 x
109 CFU of a freeze-dried formulation of the S. typhi (Ty2 aroC ̄
ssaV ̄) ZH9 vaccine. In the third study (Study MS01.04) 32 subjects received 5
x109 CFU of freeze-dried S. typhi (Ty2 aroC ̄ ssaV ̄) ZH9 in one of
two different Presentation solutions (16 per group). These studies indicate
that the vaccine is highly immunogenic at a single dose with a good safety
profile. The immunogenicity achieved with one dose is comparable to that
obtained after 4 doses of the currently licensed oral typhoid vaccine.



Study MS01.03 was a placebo controlled, double blind, out-patient, single dose,
dose escalating study conducted under an Investigational New Drug (IND). The
study was designed to determine the safety, tolerability and immunogenicity of
three dose levels of the vaccine which consisted of a freeze-dried formulation
of the live attenuated vaccine strain S. typhi (Ty2 aroC ̄ ssaV ̄) ZH9 and
excipients. A total of 60 healthy adult volunteers were recruited in 3 cohorts
of 20. In each cohort, 16 subjects were randomized to receive vaccine and 4 to
receive placebo. The cohorts were dosed sequentially such that the first
cohort received a single dose of 5x107 CFU of S. typhi (Ty2 aroC ̄
ssaV ̄) ZH9 or placebo, the second cohort received 5x108 CFU of S.
typhi (Ty2 aroC ̄ ssaV ̄) ZH9 or placebo and the third cohort received
5x109 CFU of S. typhi (Ty2 aroC ̄ ssaV ̄) ZH9 or placebo. The vaccine
or placebo was administered in 50ml 2% bicarbonate following the prior
ingestion of a volume of 2% bicarbonate to neutralise stomach acid.



The important consideration for safety of a live, attenuated strain of S. typhi
is that following ingestion the strain is not able to disseminate throughout
the body and give rise to bacteraemia or shed persistently from the gut. The
safety monitoring was designed to show that this did not occur with MICRO-TY.



The S. typhi (Ty2 aroC ̄ ssaV ̄) ZH9 vaccine exhibited an excellent safety
profile and was found to be well tolerated by all of the subjects dosed. None
of the blood or urine cultures taken during the study were positive for S.
typhi (Ty2 aroC ̄ ssaV ̄) ZH9. Shedding of S. typhi (Ty2 aroC ̄ ssaV ̄) ZH9 in the
stools of the subjects did not continue beyond 6 days for any subject, at any
of the three dose levels. The number of subjects shedding increased with
increasing dose level.



There were no serious adverse events (SAEs) related to study medication and
there was no statistically significant difference in the incidence of adverse
events (AEs) between subjects receiving the vaccine and those who received
placebo.



The immune responses measured were the ability to elicit serum IgG antibody
against LPS (humoral immune response), and the presence of gut derived anti-LPS
lgA antibody secreting cells in the blood, which be indicative of the priming
of the gut mucosa (mucosal immune response). The correlates of protection for
typoid are not clearly understood, hence the need to carry out an efficacy
study in order to demonstrate protection. However, for the currently licensed
oral typhoid vaccine (Vivotif, Bema vaccines) which requires four doses,
results of the two immunological assays used
in assessing this vaccine have
been found to putatively correlate with the protection conferred by different
formulations and immunisation schedules of Vivotif in field trials (6,7). The
identification of these measurements as putative immunological correlates of
protection provides an invaluable tool for use in early clinical trials
evaluating new live oral typhoid vaccines. (2,4).



In study MS01.03 all three dose levels of S. typhi (Ty2 aroC ̄ ssaV ̄) ZH9 were
shown to be immunogenic, with the highest dose level being immunogenic in all
subjects. In both the 5 x107 and 5 x 108 CFU dose groups
9 (56%) subjects in each group mounted an immune response detected by either an
anti-LPS ELISPOT response on Day 7 or an anti-LPS serum IgG response on Day 28.
This number increased to 16 (100%) in the 5 x 109 CFU dose group.
None of the subjects that received placebo mounted an immunological response
against S. typhi (Ty2 aroC ̄ ssaV ̄) ZH9.







50









 










The vaccine presentation used in this study requires preparation in
non-chlorinated water and involve pre-dosing with a volume of buffer prior to
vaccine administration; this is not a convenient method of preparation and
administration. The purpose of study MS01.04 was to assess safety and
immunogenicity following administration using a presentation that will be more
convenient to prepare and administer; it can be prepared in any water and
pre-dosing with a volume of buffer will not be required. This presentation
will be suitable for commercialisation. Study MS01.04 was performed in the US
under the IND. It was an open label, single oral dose (5 x 109
CFU), out patient study involving 32 healthy adult volunteers. 16 subjects
were vaccinated using the presentation used for study MS01.03 (Presentation 1)
and 16 were vaccinated using the new presentation (Presentation 2).



The database for this study was locked in February 2004 and the data are
currently being analysed. Preliminary results are summarised below:



S. typhi (Ty2 aroC ̄ ssaV ̄) ZH9 demonstrated an excellent safety profile. There
were no serious or severe adverse events reported during the study. No
subjects reported a fever considered attributable to the vaccine, there were no
bacteraemia, no persistent shedding in stools (no subject shed beyond day 6),
and no clinically significant changes in haematological and biochemical
profiles.



An immune response was elicited in the majority of subjects following
administration of the vaccine and there was no evidence of a difference between
the presentation groups in the proportion of subjects showing an immunogenic
response detected in either the ELISA or ELISPOT assay; fifteen subjects (94%)
who received the vaccine using Presentation 1 showed a response; and fourteen
subjects (93%) who received the vaccine using Presentation 2 showed a response.



Microscience is also planning to carry out a clinical trial in South Korean
healthy adult volunteers during Q4 of 2004. This will be similar in design to
the first study that will be carried out in Vietnam. It is designed to
evaluate the safety and immunogenicity of a single dose of the intended
commercial dose of the vaccine in 28 healthy Asian volunteers in South Korea.
It will be blinded and placebo controlled (16 will receive active and 12
placebo). This study is at an advanced stage of planning and Microscience is
now committed to it. It was originally considered that it would be necessary
to carry out this study in order to provide comfort to the Vietnamese
authorities that safety and immunogenicity had been demonstrated in an Asian
population prior to being able to move the programme to Vietnam. However,
further discussion with the Wellcome Trust Unit in Vietnam indicates that the
initiation of the first study in Vietnam will not be dependent on results from
this study. Nevertheless, it is considered that initiating a study in the
region ahead of the first Vietnam study will be very helpful in securing
regulatory approval in Vietnam and, together with the studies in Vietnam it
will also provide valuable information on the uptake of the vaccine in
individuals of different genetic backgrounds.



The study will be performed at the Clinical Trial Centre based at Seoul
National University (SNU), South Korea. Ethics approval submissions have been
made and initial discussions have taken place with the Korean FDA. A
submission to Korean FDA is being made on the 30th June 2004. It is
planned to dose the first subject during the first week of October 2004.
Initiation of studies in Viet Nam is not dependant on data from this study in
Korea.



In summary, Microscience has developed a novel single dose oral vaccine that
has shown to be safe and immunogenic in healthy U.K. and North American
volunteers. There is clearly an unmet medical need in the market for a vaccine
that can overcome the compliance issues associated with multi-dose vaccines,
provide good immunological memory after
a single dose and potentially have
increased efficacy. Such a vaccine could potentially have a big impact on the
control of typhoid in endemic areas and also represent a big improvement for
prevention of typhoid to traveller’s to those areas.



It is considered that the Microscience product is the lead improved typhoid
vaccine in development. It has been developed under a Company sponsored IND
and is now in Phase II development in outpatient studies in the US. The
clinical studies have used a product manufactured from a process that is
capable of being commercialised and it is delivered in a commercial
presentation that is acceptable to regulatory authorities.








51









 








			
	Name of applicant:	 	[**]






	(d)	 	Describe the workplan (this should not be more than four pages, excluding the project
timeline)





Cover experimental design and methods to be used in this investigation.




	 	•	 	Identify up to three scientific objectives clearly within the workplan.
	 
	 	•	 	Present the project timescale visually as a Gantt chart or other project timeline
profile as a one-page appendix to this application form.





The project timescale is presented as Appendix B.








Objective 1. Initiation of a Phase II programme in Viet Nam in healthy adult volunteers and children




Objectives/key tasks




	 	•	 	Identification of site. Responsibility of the clinical investigators [**].
It is important that phase II safety and immunogenicity data is generated in subjects
representative of the target population for the field study. It is therefore intended
that a number of the phase II studies will be performed in the endemic region in the
Mekong Delta. However, at least the first study, in adult volunteers, will be undertaken
under well-controlled conditions at the Oxford University Clinical Research Unit at the
Hospital of Tropical Diseases in Ho Chi Minh City. This will ensure that technology is
transferred, staff are trained and the regulatory approval process is undertaken as
efficiently as possible, prior to moving the programme into the endemic region. Once
vaccine safety has been adequately demonstrated in this study approval will be sought to
perform subsequent studies in the endemic region.
	 
	 	•	 	Clinical protocol development. Individual protocols will be written for each of the
studies. The protocols will be owned by Microscience but developed jointly by Microscience and
the clinical investigators ([**]).
	 
	 	•	 	Regulatory approval. Microscience will be responsible for obtaining regulatory approval
for the clinical studies and for field site development. Approval will be sought from both the
Vietnamese and US regulatory agencies, as it is intended that the clinical studies will be
performed under the US IND that is held for this product by Microscience.
	 
	 	•	 	Local ethics approval. The clinical investigators ([**]) will be responsible for
obtaining ethics approval from the local Independent Review Board (IRB). Microscience and the
clinical investigators ([**]) will be responsible for preparing the documentation required for
submission.
	 
	 	•	 	Assay transfer. Assay transfer from Microscience to the Hospital for Tropical Diseases is
the responsibility of both parties and is expected to take 1 month. The immunoassays being used
for these studies have been standardised at Microscience. Assay transfer will ensure that assay
performance is comparable at the Hospital for Tropical Diseases, at Microscience and in previous
clinical studies. The process involves performing the assays multiple times using reference
samples. Transfer will be considered successful once an analyst has performed a pre-defined
number of assays that have each met the validity criteria.
	 
	 	•	 	Manufacture and release of clinical material. Responsibility of Microscience.





The clinical material will be vaccine, placebo and [**], manufactured to cGMP. [**]



Adult study. It is anticipated that existing batches of vaccine, placebo and [**] will be
used for the adult study; only packaging and labelling will be required for this study.
Following review of packaging and labelling batch records and receipt of regulatory and
ethics approval, the material will be released by Microscience for use in the clinic.



Studies in children. New batches of vaccine and placebo will be manufactured in Q1 2005
for the studies in children. Following packaging and labelling, review of manufacturing
batch records and receipt of regulatory and ethics approval, the material will be
released by Microscience for use in the clinic.



Screening and recruitment of subjects. Responsibility of the clinical investigators ([**]). To begin
once regulatory and ethics approval have been obtained. For each subject screening has to occur within
28 days of dosing. All efforts will be put in place to obtain written consent that is informed and
given voluntarily as described in Appendix C.







52









 






			
	Name of applicant:	 	[**]











	 	(d)	 	Workplan (continued)





Objective 2. Preparation of field site for Phase III study




Objectives/key tasks




	 	•	 	Identification of site. [**] will have joint responsibility.





The decision as to which area will be the site for the efficacy study and therefore for surveillance
will be based on known levels of incidence as defined by current government statistics, predicted
levels of incidence and the ease with which the required infrastructure can be put in place. The
site will be in the Mekong Delta region of Viet Nam. This area has been chosen because population
based surveillance studies for typhoid fever have previously been carried out in this region in
1995/1996. (8) It was found that the incidence level was high (overall it was 198 per 109
of the general population). The highest attack rate was among the 5-9 year olds and lowest in the
>30 year olds. It was concluded from these studies that typhoid fever is highly endemic in Viet
Nam and is a significant disease in both pre-school and school aged children. A region in the Mekong
Delta [**] has been selected for this proposal.



A typhoid surveillance study will be conducted in the proposed field-site and data will be collected
for at least one year prior to phase III immunization commencing and will continue throughout the
duration of the efficacy study. The end-point of the pre-study surveillance will be a rate of
incidence of typhoid fever in the study population. These data will be used to determine the number
of subjects to be entered into the phase III efficacy study.




	 	•	 	Establishment of infrastucture. [**] will have joint responsibility.
	 
	 	•	 	Perform Census. [**]will have joint responsibility.





A census will be performed in the study area. [**] Each of these households and each individual
residing in the household is given a unique identification number (ID#), which is used for all
interactions that occur as part of the study. ID numbers will be allocated based on the serial
number of the census form, and the sequential order within each household. The aims of the census
will be as follows: To assign a unique study number to each household




	 	•	 	To assign a unique study identification number of each individual resident in the
household
	 
	 	•	 	To obtain base-line data on socio-economic status, health seeking behaviour, prior
typhoid vaccine usage and potential typhoid risk factors
	 
	 	•	 	To provide the household members with information on the project






	 	•	 	Establish and provide training in diagnostic tools. [**] will have joint responsibility.
	 
	 	•	 	Disease surveillance, [**] will have joint responsibility.





The surveillance system will rely on patients attending existing healthcare facilities in the endemic
region (government health care facilities and participating private healthcare physicians). This
healthcare facility-based passive surveillance system will be aimed at detecting the majority of
reported cases of typhoid fever among study participants seeking medical care. Medical personnel
will interview, examine, and obtain a venous blood specimen for laboratory investigation from all
patients living in the study area with [**]



All relevant clinical information will be recorded using standard procedures and will include: date
and time of examination; name; study ID number; age and gender; full address; name of head of
household; number of days since disease began; symptoms and signs of the disease. The venous blood
sample will be taken to identify the presence of S. typhi by blood culture. Serum will also be taken
for typhoid fever serological assays.



Typhoid fever proven cases will be given antibiotic treatment as appropriate. It is anticipated that
S. typhi resistance patterns will be monitored regularly throughout the study.



A crucial feature of the surveillance programme will be the accurate identification of all patients
attending healthcare facilities, who are study participants. To accomplish this, each clinical
supervisor will attempt to identify patient ID numbers using a computer search programme (for names,
age ranges, dates of birth, sex, names of the head of households).



Additionally, all culture-proven cases and positive serological cases will be visited at home to
confirm the identification of the patient; to assess clinical progress; to assess any typhoid
fever-related disability; to determine typhoid carrier status and to apply a verbal autopsy when
needed. Culture-proven typhoid fever cases will be visited [**] after onset of illness. Follow-up
questionnaires will be completed at each visit. Stool samples will also be collected at the end of
the post-immunization [**] year follow-up on all typhoid fever cases during a home visit, with the
aim of identifying typhoid carriers.








53










 










Objective 3. Demonstration of safety, tolerability and immunogenicity in Vietnamese adults and children



The clinical programme will involve Vietnamese subjects of a broad age range (approximately 30-5 years)
and will be run as a series of age-descending studies as it will be important to demonstrate that the
vaccine is safe when administered to adults and adolescents prior to administering it to children.
Volunteers will be stratified into three different age brackets: adults (18-30 years); older children
(10-18 years); young children (5-10 years).



A. Study to demonstrate safety, tolerability and immunogenicity in healthy Vietnamese adults





The purpose of the study is to evaluate the immunogenicity and safety of [**] S. typhi (Ty2
aroC ̄
 ssaV ̄
) ZH9 oral typhoid vaccine in approximately [**] healthy adult volunteers (age 18 –
30 years inclusive) from Viet Nam. The study will be a single centre, single-blind,
placebo-controlled, randomised study. The study schedule is show in Table 12.1. The study
design will be such that there will be two groups of subjects, Group 1 will receive vaccine and
Group 2 will receive placebo.


Table 12.1 Study schedule for study in healthy adult volunteers




	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	Visit	 	Screen	 	1	 	2	 	3	 	4	 	5	 	6
	Day

	 	-28 to – 2
	 	 	0	 	 	 	1	 	 	 	7	 	 	 	10	 	 	 	14	 	 	 	28	 
	[**]

	 	[**]	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	[**]

	 	[**]
	 	 	[**]	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	[**]

	 	[**]
	 	 	[**]	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	[**]

	 	[**]	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	[**]

	 	[**]
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	[**]	 
	[**]

	 	[**]
	 	 	[**]	 	 	 	[**]	 	 	 	[**]	 	 	 	[**]	 	 	 	[**]	 	 	 	[**]	 
	[**]

	 	[**]	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	[**]

	 	 	 	 	[**]	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	[**]

	 	 	 	 	[**]	 	 	 	 	 	 	 	[**]	 	 	 	 	 	 	 	 	 	 	 	 	 
	[**]

	 	 	 	 	 	 	 	 	[**]	 	 	 	[**]	 	 	 	[**]	 	 	 	[**]	 	 	 	 	 
	[**]

	 	 	 	 	[**]	 	 	 	[**]	 	 	 	[**]	 	 	 	[**]	 	 	 	[**]	 	 	 	[**]	 
	[**]

	 	 	 	 	[**]	 	 	 	[**]	 	 	 	[**]	 	 	 	[**]	 	 	 	[**]	 	 	 	[**]	 
	[**]

	 	 	 	 	[**]	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	[**]
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	[**]

	 	[**]
	 	 	[**]	 	 	 	 	 	 	 	[**]	 	 	 	 	 	 	 	[**]	 	 	 	[**]	 
	[**]

	 	[**]
	 	 	[**]	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	[**]	 
	[**]

	 	[**]
	 	 	[**]	 	 	 	 	 	 	 	[**]	 	 	 	 	 	 	 	 	 	 	 	 	 
	[**]

	 	[**]
	 	 	[**]	 	 	 	 	 	 	 	[**]	 	 	 	[**]	 	 	 	 	 	 	 	 	 
	[**]
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	[**]

	 	 	 	 	[**]	 	 	 	 	 	 	 	[**]	 	 	 	 	 	 	 	 	 	 	 	 	 
	[**]

	 	 	 	 	[**]	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	[**]	 	 	 	[**]	 








54









 












Objectives/key tasks




	 	•	 	Dosing. Responsibility of the clinical investigators ([**]).






Following completion of the screening assessments subjects who satisfy the study entry criteria will be
randomised to one of the two treatment groups and will receive medication on Day 0. Subjects will be split
into at least [**] cohorts for dosing. The time between dosing each cohort may be at least [**] weeks; it
may therefore take [**] weeks to complete dosing of all subjects. The size of the cohorts will be governed
by the number of [**] samples that can be processed on one occasion. In each cohort some subjects will
receive vaccine and some will receive placebo. The vaccine will be nominal dose of [**] typhoid vaccine
administered in [**] of presentation solution. Placebo will also be administered in [**] of presentation
solution. Vaccine will be prepared in the pharmacy and administered to the subjects within [**] minutes of
preparation.




Subjects will return to the investigative site on study Days [**] for assessment of safety and immunogenicity
and to provide blood, urine and stool samples as required. Subjects will record their temperatures on a
Diary Card for the first [**] days following dosing and will return to the clinic for additional visits
should they develop fever.




	 	•	 	Evaluation of safety. Responsibility for the clinical investigators ([**]).






The primary safety endpoints for the study are the proportion of subjects:




	 	•	 	reporting adverse events during the study, particularly a fever of more than [**]° C,
attributable to the study medication.






The secondary safety endpoints are the proportion of subjects:




	 	•	 	withdrawn from the study due to adverse events, including bacteraemia attributed to study
medication
	 
	 	•	 	demonstrating bacteraemia, attributable to the study medication
	 
	 	•	 	demonstrating persistent faecal shedding ([**]) of
S. typhi (Ty2 aroC ̄
 ssaV ̄
) ZH9, in stools
	 
	 	•	 	with changes in laboratory parameters from Day 0 to post treatment which are considered clinically
significant






	 	•	 	Completion of immunoassays. Responsibility of the clinical investigators ([**]).






As in previous studies in the UK and US, immunogenicity will be assessed by measuring immune response against
S. typhi lipopolysaccharide (LPS); using the [**] to measure numbers of circulating antibody secreting cells
producing anti-LPS IgA, and an ELISA assay to measure serum IgG response against LPS. Subjects will be
considered to have an immune response if they achieve the following: a [**].




[**]. ELISA assays will be performed on frozen serum samples. It is anticipated that data from the pivotal
immunoassays, [**] to detect secretory IgA against LPS and ELISA to detect serum IgG against LPS, will be
available for review within [**] weeks of dosing the first subject.




	 	•	 	Monitoring of study (safety and GCP). Responsibility of Microscience.
	 
	 	•	 	Management and validation of data. Responsibility of Microscience.




Once a full dataset is available from safety assessments and from the pivotal immunoassays, the data will be evaluated by
Microscience, the clinical investigators, the regulatory agencies and by the local ethics committee to establish whether it
provides adequate confidence to progress to evaluation of safety and immunogenicity in children.





B. Study to demonstrate safety, tolerability and immunogenicity in Vietnamese children.




This section of the programme will involve a series of age-descending studies. The purpose is to evaluate safety and
immunogenicity of the vaccine in children from 5-18 years. Approximately [**] children will be involved, stratified
into 2 age groups: 10-18 years, approximately [**] subjects; 5-10 years, approximately [**] subjects.




The studies will be single centre, single-blind, placebo-controlled, randomised studies. The basic study schedules will
be as for the adult study shown in Table 12.1.







55









 











Objectives/key tasks for each study




	 	•	 	Dosing. Responsibility of the clinical investigators ([**]).

Group 10-18 – years it is anticipated that data from the adult study will support
the use of the same dose level, [**] dose, and formulation of vaccine as was
administered to adults.
	 
	 	 	 	Group 5-10 years — evaluation of safety data from the study in 10-18 year olds
will determine whether dose escalation will be required for this study. Dose
escalation will require an additional group of subjects who will receive a lower
vaccine dose level (likely to be [**]).
	 
	 	•	 	Evaluation of safety. Responsibility of the clinical investigators ([**]).

As for adult study.
	 
	 	•	 	Completion of Immunoassays. Responsibility of the clinical investigators
([**]).
	 
	 	 	 	The assays used will be the same as for the adult study.
	 
	 	•	 	Monitoring of study (safety and GCP). Responsibility of Microscience.
	 
	 	•	 	Management and validation of data. Responsibility of Microscience.




Once a full dataset is available from safety assessments and from the pivotal immunoassays,
the data will be evaluated to establish whether it is adequate to support entry of children
into the phase III field study.

 








56









 






	 	 	 	 	 
	 	Name of applicant:	 	 	          [**]	 
	 	 	 	 	 





Q13 Detail the commercial opportunities arising from this proposal:





Please refer to the guidance notes before completing. This section should be completed with input from the
technology transfer office/group and address the areas outlined below. This section should be no more than 41/2
pages.




	 	(a)	 	Intellectual property and freedom to operate (suggested 11/2 pages)
	 
	 	(b)	 	Competitive position (suggested 1 page)
	 
	 	(c)	 	Managing, monitoring and reporting the project (suggested 1/2 page)
	 
	 	(d)	 	Commercialization strategy (suggested 11/2 pages)




   Following appropriate protection of any arising intellectual property, is it intended to publish the findings
of this research? o Yes       oNo







(a) Intellectual property and freedom to operate



The product is a mutated Salmonella bacterium. The ssaV gene and the aroC genes are deleted. The ssaV gene was
identified as part of the Salmonella Pathogenicity Island-2 (SPI-2) using Signature Tagged Mutagenesis (STM). Both the
method (STM) and the pathogenicity island, including its genes and attenuated mutants, are claimed in WO96/17951. The
particular combination of an ssaV mutation with an aroC mutation is claimed in WO00/68261.



Relevant claims relating to this product and directed to genes of the SPI-2 region and attenuated mutants were
initially present in WO 96/17951 and WO 00/68261. The major claims As mentioned above, these claims were subsequently
filed in divisional applications which have now proceeded to grant in both the US and the EPO. In Europe, the claims
provide coverage for particular DNA sequences from Salmonella virulence genes; antisense nucleic acids; bacteria having
mutations in one or more particular virulence genes (one of these being ssaV); virulence genes; promoters of virulence
genes; polypeptides; pharmaceutical compositions and methods of identifying compounds which reduce the ability of a
microorganism to adapt to a particular environment involving selecting compounds which interfere with the function of a
gene covered by the earlier claim. Similar claims have been granted to Microscience and Imperial in the US.



A further European divisional application has also been filed. This divisional application, no. 01205191.8, is also
registered in the joint names of Imperial and Microscience. It is at a relatively early stage of prosecution but
could, conceivably, provide useful additional peripheral protein in relation to this product. This divisional
application is directed to particular DNA sequences isolated from a Salmonella genome and virulence genes containing
such DNA; a method of identifying a compound which reduces the ability of a microorganism to adapt to a particular
environment, and compounds identified by the method; the use of such a compound in the manufacture of a medicament for
treating infection of a host organism with a particular microorganism; molecules which selectively interact with and
inhibit a virulence gene; use of such compounds in manufacturing medicaments for treating hosts which have or are
susceptible to an infection with the microorganism; mutant bacteria; vaccines and pharmaceutical compositions; methods
of making mutant microrganisms; and methods of making a pharmaceutical formulation of a mutant microorganism. Certain
claims, eg relating to DNA sequences or to antisense nucleic acids capable of interacting with and inhibiting virulence
genes, have had only ‘technolocial background’ references cited against them in the EPO search report, indicating that
at least some of the claimed subject matter is likely to be patentable.



The typhoid vaccine product is also covered by international application no. PCT/GB00/01749. This application has
entered a very wide range of national phases. This reflects the number of territories in which typhoid is endemic.



In summary, Microscience has already obtained effective protection for its typhoid vaccine product. Further related
protection can also be expected in many territories.









57









 







b) Competitive position



The principal vaccines for typhoid are currently an injectable purified
capsular polysaccharide vaccine (“Vi vaccine”) and a live attenuated oral
vaccine (Vivotif)



The Vi vaccine has demonstrated 55-74% efficacy and requires
re-vaccination every two to three years. Typically for a polysaccharide
vaccine the immune response to Vi is age related and it is poorly
immunogenic in young children. It is also a T cell independent antigen
and so is not able to boost a primary immune response. A Vi-conjugate
vaccine is in early development in which Vi is bound to a non-toxic
recombinant protein that is antigenically identical to Pseudomonas
aeruginosa exotoxin A. This has been tested in a field study in Viet Nam
but not in a final formulation. However, this is not expected to be a
single dose vaccine.



The live oral vaccine was constructed in the pre-molecular biology era.
As a consequence, the basis of the attenuation is not fully understood.
The vaccination regimen for the US licensed oral vaccine product consists
of four doses, one to be taken every other day, which achieves protection
in approximately 60 – 70% of recipients.



There is clearly an unmet medical need in the market for a vaccine that
can overcome the compliance issues associated with multi-dose vaccines,
provide good immunological memory after a single dose and potentially
have increased efficacy. Such a vaccine could potentially have a big
impact on the control of typhoid in endemic areas and also represent a
big improvement for prevention of typhoid to traveller’s to those areas.



In terms of other improved vaccines being developed. Avant
Immunotherapeutics Inc. and Acambis plc are developing an oral single
dose live attenuated typhoid vaccine. Avant were scheduled to commence a
Phase I inpatient study (sponsored by NIAID) in 2H 2003. It is not known
whether this study was initiated. Acambis have recently decided, for
commercial reasons, not to invest further in their vaccine programme and
they are seeking to outlicense the vaccine. This vaccine has been in
development for some years and product from a commercially viable process
has not yet been tested in the clinic.



The advanced product development package associated with the Microscience
vaccine represents a real competitive advantage over other products in
development.



Vaccines are biologicals, and as such present particular challenges in
development as compared to conventional drug products. Unlike small
molecules or defined peptides, they are much more difficult to
characterize and control, particularly if the product is a whole cell
vaccine or complex protein. Because of this, how the product is derived,
characterised and manufactured becomes an important part of the product
profile. The introduction of changes in product development, for example
in the cell banking or manufacturing process are regarded as changes in
the product. Therefore, clinical studies may have to be repeated if
changes are introduced, particularly if there is no detailed product
characterization data to support comparability of products.



One of the driving philosophies behind Microscience has been ‘know your
product early and be the experts’. This means that prior to any Phase I
study, cell banks are established from which the product will be derived,
detailed product characterization data are generated, assays are
developed for controlling the process and product release and the basis
of a robust manufacturing process capable of being commercialized is in
place. This has ensured that the product used in the early pre-clinical
and clinical studies has essentially the same characteristics as that
intended for marketing and that there will be no delays in moving into
the later stages of clinical development



In summary it is considered that the Microscience product is the lead
improved typhoid vaccine in development. It has been developed under a
Company sponsored IND and is now in Phase II development in outpatient
studies in the US. The clinical studies have used a product manufactured
from a process that is capable of being commercialised and it is
delivered in a commercial presentation that is acceptable to regulatory
authorities.



Microscience’s current target market is both business and leisure
travellers from industrialised countries to typhoid risk regions. The US
Centres for Disease Control and Prevention (CDC) states that typhoid
vaccination is recommended for travellers to areas where there is a
recognised risk of exposure to S.typhi. It regards risk as greatest to
travellers to the Indian subcontinent and other low-income countries (in
Asia, Africa and Central and South America)




58









 








	 	 	 	 	 
	 	Name of applicant:	 	 	          [**]	 
	 	 	 	 	 








Q13 Detail the commercial opportunities arising from this proposal (continued):




59









 











The market is driven by the number of travellers to the typhoid risk
regions. During 2000, there were a total of approximately 40 million
visits from the US, Europe and Japan to destinations with a risk of
typhoid in Africa, Asia and Central and South America. However, it must
be noted that this number has been negatively impacted by world events
since then.



However, the greatest need for the vaccine is in the endemic areas
themselves. Typhoid fever remains a very significant global health
problem with an estimated 17 to 33 million cases occurring worldwide
annually resulting in 600,000 deaths throughout the world, virtually all
these cases occur in the developing world. In the last few years there
has been the worrying development and global spread of bacteria that are
resistant to all affordable antibiotics. Over 90% of isolates in
Southern Viet Nam are resistant to all first line antibiotics making the
need for an effective and affordable vaccine more urgent. There are
licensed vaccines available to prevent typhoid fever but these are less
than ideal for control of typhoid fever in developing countries.



The current market for typhoid vaccines is about $100 million in US and
Europe and around $120 million worldwide. Provided its efficacy is
superior to existing vaccines, it is well tolerated and it is an oral
single dose, Microscience’s vaccine should be competitively positioned to
gain share in the travellers’ market from the existing typhoid vaccines.



c) Managing, monitoring and reporting the project



The overall management of the project will be the responsibility of
Microscience. Microscience has a full time experienced, project manager
who leads the existing project team and has been responsible for the
development of the oral typhoid vaccine to date. The project team
members include experienced development staff from CMC (chemistry
manufacturing and control) pre-clinical, regulatory and clinical. The
team is further supported by external specialists such as clinical
research organisations that handle monitoring, GCP (good clinical
practice) compliance and clinical data bases. It is intended that the
scientific co-applicants will be integrated into the existing project
team and the tasks coordinated through this structure which already has a
proven track record in developing this programme. Regular project
meetings will be held which will monitor the progress of the project
against the project plan and deal with issues as they arise. Project
reports will be issues on a monthly basis to the Wellcome Trust in a
format to be agreed.



d) Planned commercial exit



The commercial market for typhoid vaccines is not large and it is
difficult for Microscience to justify funding the whole programme
required to gain approval of the product, either as a travellers vaccine,
or in developing countries, given that the Company has a number of more
commercially attractive vaccines in the portfolio. Acambis, who had a
similar product in development, recently announced that they are not
going to invest further resources in the project because they do not
believe that they will generate the required return on investment.



However, Microscience recognises the importance of this vaccine in
providing substantial healthcare benefits in the developing world and
would like to ensure that if the vaccine is successful, those benefits
are delivered.



The route to commercialisation of the vaccine whether it is for
travellers or the developing world will involve carrying out a large
efficacy study in a country where typhoid is endemic. The STA proposal
is critical for taking the first steps in this process and addressing one
of the key issues relating to transfer of vaccines from the developed to
the developing world, that is whether the safety and immunogenicity
profiles will be similar. It will be difficult to obtain further
investment into the project until this key question has been answered.



If the vaccine proves to be successful in the stepping stone studies in
Viet Nam it should provide leverage for obtaining additional funding,
either from commercial or NGO sources.



It is therefore intended to use these data to facilitate interactions
with other NGO funding groups in order to provide funding for the Phase
III efficacy study that it is intended to initiate in 2006. All studies
in Viet Nam will be carried out under a US IND as well as under the
appropriate authority in Viet Nam in order that it is possible to
eventually submit a Biologics License Application to the FDA for approval
of the product in [**]. In parallel, with appropriate funding and
technology transfer activities it should also be possible to get the
product manufactured and approved in developing countries such as Vietnam
where the vaccine has the potential to deliver considerable health care
benefits.







60









 







	 	 	 	 	 
	 	 	 	 	          [**]	 
	 	 	 	 	 









Q13 Detail the commercial opportunities arising from this proposal (continued):










      







61









 





	 	 	 	 	 
	 	Name of applicant:	 	 	          [**]	 
	 	 	 	 	 







	 	 	 
	Q14

	 	References
	 
	 

	 	Please give citations in full including titles of papers and all authors.












	 	1.	 	Chatfield, S.N., Roberts, M., Li, J-L, Starns, A. and Dougan, G. 1994. The use of
live attenuated Salmonella for oral vaccination. In: Recombinant Vaccines in Vaccine
Development: Dev. Biol. Stand. Basel, Karger 82, 35-42.
	 
	 	2.	 	Tacket, C.O, Sztein, M.B., Losonsky, G.A., Wasserman, S.S., Nataro, J.P., Edelman
R., Pickard, D., Dougan, G., Chatfield, S.N. and Levine, M.M. 1997. Safety of live
oral Salmonella typhi vaccine strains with deletions in htrA and aroC aroD and immune
response in humans. Infect. Immun. 65, (2) p.452-456.
	 
	 	3.	 	Shea, J.E, Buezon, C.R, Gleeson C, Mundy R, Holden, D.W. Influence of the
Salmonella typhimurium Pathogencity isaland 2 type III secretion system on bacterial
growth in the mouse. Infect. Immun. 1999, 67(1): 213-219.
	 
	 	4.	 	Hindle Z, Chatfield SN, Phillimore J, Bentley M, Johnson J, Cosgrove CA,
Ghaem-Maghami M, Sexton A, Khan M, Brennan FR, Everest P, Wu T, Pickard D, Holden DW,
Dougan G, Griffin GE, House D, Santangelo JD, Khan SA, Shea JE, Feldman RG, Lewis DJ
Characterization of Salmonella enterica derivatives harboring defined aroC and
Salmonella pathogenicity island 2 type III secretion system (ssaV) mutations by
immunization of healthy volunteers. Infect. Immun. 2002 Jul:70(7):3457-67..
	 
	 	5.	 	Shahid A Khan, Richard Stratford, Tao Wu, Nicola McKelvie, Trevor Bellaby, Zoe
Hindle, Katharine A Sinha, Shayne Eltze, Piero Mastronel, Derek Pickard, Gordon
Dougan, Steven N Chatfield, Frank R Brennan Salmonella typhi and S. typhimurium
derivatives harbouring deletions in aromatic biosynthesis and Salmonella
pathogenicity island-2 (SPI-2) genes as vaccines and vectors Vaccine 21 (2003)
538-548
	 
	 	6.	 	Kantele, A. Antibody secreting cells in the evaluation of the immunogencicty of an
oral vaccine. Vaccine. 1990 (8) 321-326
	 
	 	7.	 	Ferreccio. C, Levine. M.M, Rodriguez, H, Contreras. R, Chilean Typhoid Committee.
	 
	 	 	 	J. Infect. Dis 1989 (159) 4 766-769
	 
	 	8.	 	Feng-Ying C. Lin, Vo Anh Ho, Phan Van Bay, Hguyen Thi Thanh Thuy, Dolores Brlyla,
Tran Cong Thanh, Ha Ba Khiem, Dang Duc Trach and John B. Robbins. The epidemiology
of typhoid fever in the Dong Tap Province, Mekong Delta Region of Vietnam. J. Trop.
Med. Hyg. 2000 62 (5), 2000 644-648.





     Copies of references provided in Appendix D.












62









 





Q15 Research on human participants or human tissue




	 	 	 	 	 	 	 
	(a)

	 	Does your project involve the use of human participants or human
tissue?
	 	R Yes
	 	£ No
	 
	 	 	 	 	 	 
	 

	 	Please confirm that appropriate informed consent has been/will be
obtained for patenting.
	 	R Yes
	 	£ No
	 
	 	 	 	 	 	 
	 

	 	Please confirm that appropriate informed consent has been/will be
obtained for commercial use.	 	 	 	 
	 
	 	 	 	 	 	 
	 

	 	If yes, please refer to guidance notes. If the project
includes studies on patients being cared for by the NHS, please
also answer Q16.
	 	R Yes
	 	£ No
	 
	 	 	 	 	 	 
	(b)

	 	Does your project involve the use of human participants or other human
tissue, 

outside the UK?
	 	R Yes
	 	£ No
	 
	 	 	 	 	 	 
	 

	 	Please confirm that appropriate informed consent has been/will be
obtained for patenting.
	 	R Yes
	 	£ No
	 
	 	 	 	 	 	 
	 

	 	Please confirm that appropriate informed consent has been/will be
obtained for commercial use.	 	R Yes
	 	£ No
	 
	 	 	 	 	 	 
	 

	 	If yes, please refer to guidance notes.
	 	 	 	 
	 
	 	 	 	 	 	 
	(c)

	 	Does your project involve the use of human embryos requiring a licence
from the Human Fertilisation and Embryology Authority (HFEA)?	 	£ Yes
	 	R No
	 
	 	 	 	 	 	 
	 

	 	If yes, please refer to guidance notes.
	 	 	 	 
	 
	 	 	 	 	 	 
	(d)

	 	Does your proposal involve research on gene therapy which requires
regulatory approval?	 	£ Yes
	 	R No
	 
	 	 	 	 	 	 
	 

	 	If yes, please refer to guidance notes.
	 	 	 	 






63









 






Q16 Research using NHS facilities or patients




	 	 	 	 	 	 	 
	 

	 	 
	 	£ Yes
	 	R No





(a) in the course of your
project, do you propose to use
facilities within the National
Health Service and/or does your
research involve patients being
cared for by the NHS?





If yes, please confirm that your project is in accordance with the principles of the Statement of
Partnership on Non-Commercial Research and Development in the NHS in England (or the corresponding
statements




in Northern Ireland, Scotland and Wales), distributed with Department of Health EL(97)77, dated
27 November 1997 (a link to this site can be found in the associated guidance notes).









N/A




 







(b) Which NHS provider(s) has agreed to facilitate this research?










N/A



 


 







64









 





Q17 Experiments on animals




	 	 	 	 	 	 	 
	 

	 	Do your proposals involve the use of animals or animal tissue?
	 	£ Yes
	 	R No
	 
	 	 	 	 	 	 
	(a)If yes, do your proposals include procedures to be carried out on animals in the UK which require a Home Office Licence?	 	£ Yes	 	R No
	 
	 	 	 	 	 	 
	 

	 	If yes, has the Home Secretary granted a Project Licence under the terms and the Animals (Scientific Procedures) Act
1986, authorising the proposed experiments?
	 	£ Yes
	 	£ No
	 
	 	 	 	 	 	 
	 

	 	If yes, state the name and address of the licensee, the Project Licence reference number, date of issue and end date.	 	 	 	 












N/A




 







	 	 	 	 	 	 	 
	 

	 	Do you, or any other researchers associated with the project, hold a Personal Licence under the
Animals (Scientific Procedures) Act 1986, permitting the procedures required for the research
to be carried out?
	 	£ Yes
	 	£ No
	 
	 	 	 	 	 	 
	 

	 	If yes, state Personal Licence Reference Number and name of licence holder.	 	 	 	 












N/A




 







	 	 	 	 	 	 	 
	 

	 	If no, has an application been made for such a licence?
	 	£ Yes
	 	£ No
	 
	 	 	 	 	 	 
	 

	 	Please give a brief explanation, including the date when an application will be made.	 	 	 	 












N/A




 







	 	 	 	 	 	 	 
	(b) Do your proposals involve the use of animals or animal tissue outside the UK?	 	£ Yes	 	R No







If yes, give details of the local ethics committee approval that has been sought, relating this approval to the permission which would be required if the research were to be conducted in the UK.









N/A




 







65









 






	 	 	 	 	 
	 	Name of applicant:	 	 	          [**]	 
	 	 	 	 	 






Q18 Access to radiation sources




	 	 	 	 	 	 	 
	(a)

	 	Will the proposed research require access to either the Synchrotron Radiation
	 	£ Yes
	 	R No
	 

	 	Source (SRS) at Daresbury or the European Synchrotron Radiation Facility (ESRF) at Grenoble?	 	 	 	 
	 
	 	 	 	 	 	 
	 

	 	If yes, please complete the table below, providing details of beam time
requested and scheduling information (anticipated usage in days.) [Beam
time is counted in whole days only.]	 	 	 	 






	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	 	 	 	 	 	 	Special	 	 	 	 	 	 	 
	 	 	 	 	 	 	requirements	 	 	Total	 	 	 	 
	 	 	 	 	 	 	(single bunch,	 	 	number	 	 	Number of days per annum	 
	Synchrotron	 	Station	 	 	other specify)	 	 	of days	 	 	Year 1	 	 	Year 2	 	 	Year 3	 	 	Year 4	 	 	Year 5	 
	 
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	 
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	 
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 




(b) Please justify the station(s) and beam time requested (no more than 500 words).










N/A




 







	 	 	 	 	 	 	 	 	 
	(c)

	 	Will the proposed research require access to a neutron source?
	 	£ Yes
	 	R No
	 
	 

	 	If yes, complete Q18(a) and (b) above indicating that it is a neutron source that is required
	 	 	.	 	 	 






66









 







	 	 	 
	Name of
applicant:

	 	  [**]









	 	 	 
	Q19

	 	Related applications






	 	 	 	 	 
	(a)

	 	While this application is being considered by the Wellcome Trust, you
should not submit an application to any third party to fund the
proposed research which is the subject of this application. Please
confirm that you agree to give the Wellcome Trust exclusivity to
consider this application.
	 	þYes            o No


N/A
 
	 
	 	 	 	 
	 

	 	 	 	oYes            þ No






	 	 	 	 	 
	(b)

	 	Has this or a related application already been submitted elsewhere?
	 	N/A
 
	 
	 	 	 	 
	 

	 	If yes, to which organization? 	N/A

	 
	 	 	 	 
	 

	 	If a decision has been given, what was the result?	 	 
	 
	 	 	 	 
	 

	 	If a decision has not yet been given, when is a decision expected? (dd/mm/yy)









	 	 	

	 
	(c)	 	What proportion of
working
time do the principal
applicant
and coapplicant(s) spend
on research? (%)
	 
	 	 	



What proportion of this time
will the principal applicant
and coapplicant(s) spend
on this project? (%)











	 	 	 	 	 	 	 	 	 
	 	Name

	 	 	% Working time
 on
research
	 	 	Project time as
 %
of research
 time	 
	
 	 
	 	 	 	 	 	 	 
	
 	 
	 	 	 	 	 	 	 
	 	 
	 	 	 	 	 	 	 
	


 	 
	 	 	 	 	 	 	 
	 	 
	 	 	 	 	 	 	 
	 	 
	 	 	 	 	 	 	 
	 	 
	 	 	 	 	 	 	 
	 










	 	 	 	 	 
	(d)

	 	Will the research project be undertaken in a Wellcome Trust Clinical
Research Facility?
	 	þYes            o No






	 	 	 	 	 
	 

	 	If yes, please
specify:

	 	Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh,

Vietnam








	 	 	 	 	 
	(e)

	 	Will the research project be undertaken in a Wellcome Trust Centre?
	 	oYes            þ No






      
If yes, this application should be accompanied by a letter of support from the Director
of the Centre.



67









 






Q20 Commercial interactions




	 	 	 	 	 	 	 
	  (a)

	 	Do any of the scientific applicants hold
any directorships, equity holdings, Scientific
Advisory Board memberships or consultancy
arrangements in companies or other
organizations that may have an interest in the
results of the proposed research?
	 	R Yes
	 	£ No
	 
	 	 	 	 	 	 
	 

	 	If yes, please refer to guidance notes, give brief details and provide copies of relevant agreements.	 	 	 	 










[**]



 








	 	 	 	 	 	 	 
	  (b)

	 	Is the proposed research in whole or in part, subject to any agreements with
	 	Yes
R 
	 	£ No
	 

	 	commercial, academic or other organizations?	 	 	 	 
	 
	 

	 	If yes, give details	 	 	 	 






68









 










A consultancy agreement already exists with the International Vaccine
Institute (dated 02-12-03) which relates to the project. This was set up in
order for Microscience to receive advice on the development of clinical
strategy and to establish the field site in Vietnam. This is attached as
Appendix E.




 











69









 





	 	 	 	 	 	 	 	 	 
	Q21	 	Curriculum vitae of principal applicant
	 
	 	 	 	 	 	 	 	 
	 	 	This page should be duplicated if there is more than one applicant/coapplicant/sponsor.
	 
	 	 	 	 	 	 	 	 
	 

	 	[**]	 	  [**]

	 	[**]
	 	  [**]

	 
	 	 	 	 	 	 	 	 
	 

	 	[**]
	 	  [**]

	 	[**]
	 	  [**]

	 
	 	 	 	 	 	 	 	 
	 

	 	[**]	 	 	 	 	 	 






	 	 	 	 	 
	 

	 	  [**]    
                   
                   
                
                 
         
         
         
         
                [**]

	 	






	 	 	 	 	 
	 

	 	[**]	 	 
	 
	 	 	 	 
	 

	 	[**]
	 	  [**]

	 
	 	 	 	 
	 

	 	[**]
	 	 

	 
	 	 	 	 
	 

	 	[**]
	 	  [**]







	 	 	 	 	 	 	 	 	 
	 

	 	[**]
	 	 	 	 	 	  [**]

	 
	 	 	 	 	 	 	 	 
	 

	 	[**]	 	 	 	 	 	 






	 	 	 
	 

	 	  [**]







	 	 	 	 	 	 	 	 	 
	 

	 	[**]	 	 	 	 	 	 
	 
	 	 	 	 	 	 	 	 
	 

	 	[**]
	 	[**]
	 	[**]
	 	  [**]




	 
	 	 	 	 	 	 	 
	 

	 	 	 	[**]	 	 	 






	 	 	 	 	 	 	 	 	 
	 

	 	[**]
	 	 	 	 	 	  [**]







	 	 	 	 	 	 	 	 	 
	[**]
	 	 	 	 	 	 	 	 
	 
	 	 	 	 	 	 	 	 
	 

	 	  [**] 
                   
                   
                   
                   
                   
                   
                   
                   
         [**]

	 	 	 	 	 	 
	 
	 	 	 	 	 	 	 	 





	 	 	 	 	 	 	 
	[**]
	 	 	 	 	 	 
	 
	 	 	 	 	 	 
	 

	 	  [**]

  [**]

  [**]
  [**]
  [**]
  [**]
  [**]

	 


	 


	 

	 

	 
	 
	 
	 

	 
	 
	 
	[**]
	 
	 
	 





	 	 	 	 	 	 	 	 	 
	 

	 	[**]
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  [**]

	 
	 	 	 	 	 	 	 	 
	 

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	 	[**]	 	 	 	 	 	 






	 	 	 	 	 	 	 	 	 
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                [**]







	 	 	 	 	 
	 

	 	[**]	 	 
	 
	 	 	 	 
	 

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	 	[**]
	 	 








70









 







	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
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	 	 	[**]	 	 	 	 	 	 	 	 	 	  [**]
 
	 

	 	[**]
 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	 	 	 

	[**]
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	 	 	[**]	 	[**]	 	[**]

[**]	 	

 

	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 

	[**]	 	 	 	 	 	 	 	 	 	 	 	 	 	  [**]

	[**]
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	 	 	  [**]	      [**]


	[**]
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	                                          [**]
[**]  
	 
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	 	 	[**]	 	 	 	  [**]
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	 	 	[**]	 	 	 	  [**]
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	[**]
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	 	 	[**]	      [**]
	 	 	  

	 

	 	[**]	 	 	 	 	 	 	 	 	 	 	 	 	 	 
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[**]	 	

 








71









 







	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
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	[**]
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
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	[**]
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	                  
       [**]
[**] 
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	[**]

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	 	 [**]
                  
                           
                                             
                  
                  
       



[**]
 







72









 








	 	 	 	 	 	 	 
	 	 	 	 
	 

	 	 	[**]
	 	[**]	 
	 
	 	 	 	 	 	 
	 
	 	 	 	 	 	 
	 

	 	 	[**]
	 	[**]	 
	 
	 	 	 	 	 	 
	 
	 	 	 	 	 	 
	 	 	 	 





[**]




	 	 	 	 	 	 	 
	 	 	 	 
	 

	 	 	     [**]
	 	 	 
	 
	 	 	 	 	 	 
	 
	 	 	 	 	 	 
	 
	 	 	 	 	 	 
	 	 	 	 





Q22 Technology transfer office/group experience



Please detail relevant project management and deal-making experience of the technology transfer
office/group. Give field-specific examples if available, and details of any other experience
gained through exploitation of research arising from other Wellcome Trust awards (including
University Translation Awards).









N/A




















73









 










 






















	Q23 	 	 Curriculum vitae of named research assistant(s)
	 
	 	 	This page may be duplicated if more than one research assistant is required.





	 	 	 	 	 	 	 	 	 
	(a)

	 	Surname:
	 	 

	 	Date of  	 	 

	 
	 	 	 	 	 	 	 	 
	 

	 	Forename
	 	 

	 	Nationality: 	 	 

	 
	 	 	 	 	 	 	 	 
	(b)	 	Degrees, diplomas etc. (subject, class, university and dates):	 	 	 	 
	 
	 	 	 	 	 	 	 	 
	 	 	 







	 	 	 	 	 
	(c)	 	Current post (if not currently in employment, please give details of most recent post):
	 

	 	Position and
	 	 

	 
	 	 	 	 
	 

	 	Institution:
	 

	 
	 	 	 	 
	 

	 	Funding
	 	 







	 	 	 	 	 
	 

	 	Termination date of
	 	 

	 
	 	 	 	 
	 

	 	Current basic salary and incremental
	 	 

	 	 	Basic salary must be shown separately from any salary enhancements or other allowance






	 	 	 	 	 
	 

	 	If currently funded by a Wellcome Trust grant,
please give grant reference
number:
	 	 

	 
	 	 	 	 
	(d)

	 	Previous posts (with dates):	 	 






	 	 	 
	 

	 	 











74









 






	(e)	 	Recent publications: (List no more than five publications. Please
give citation in full, including title of paper and all authors)










      








	(f)	 	Please confirm that you have obtained the research assistant’s consent
to disclose the information provided above in accordance with the
principles set out in the Wellcome Trust Data Protection statement
which appears on this form. £




75









 











	 	 	 
	Q24

	 	Reasons for support requested
	 
	 	 
	 

	 	Please refer to guidance notes before completing this section.
	 
	 	 
	 

	 	On this page justify (a) the scientific staff requested










The detailed budget is shown in Appendix F.



Phase Two Studies at the Hospital for Tropical Diseases



These studies will build on an existing infrastructure at the Hospital for
Tropical Diseases and this will help to limit the costs. However, during the
duration of the project there will clearly need to be staff that are dedicated
to this work. We have therefore requested salaries for two Clinical
Investigators, costs for Nursing staff and two technicians, costs to the Ward
where this work will be undertaken and costs for the volunteers.



Surveillance Studies in [**] Province



The Hospital for Tropical Diseases and the Oxford University-Wellcome Trust
Unit, in Viet Nam and the International Vaccine Institute has extensive
experience of organizing surveillance studies similar to this. A full time
Clinical Epidemiologist based in Viet Nam will be essential in coordinating all
aspects of the Surveillance in [**] Province. This individual will split his
(her) time between Ho Chi Minh City and [**] Province and ensure that the data
is collected and stored appropriately. They will need to be senior enough to
take on a considerable degree of responsibility and autonomy. This is the key
appointment for this project.



The data management is a crucial point of all epidemiological studies. The IVI
has extensive experience in running such projects and that knowledge will be
vital to the success of these population based studies. We have requested
support for a Data Manager and Statistician.



From previous experience the request for Health Care Workers, Medical
Officers, Clinical Investigators, secretarial support etc is the minimum
required to undertake surveillance in a population of this size. The numbers
and skills of the individuals have been estimated from previous work in Viet
Nam and in the region.


 









76









 









			
	Q24	 	Reasons for support requested (continued)





     On this page justify (b) Materials and consumables and (c) Equipment and equipment maintenance
requested






Phase Two Studies at the Hospital for Tropical Diseases



a) Materials and consumables.



This has been estimated from similar previous studies.



b)      Equipment



This work will build on an existing infrastructure in Viet Nam and therefore
there are no equipment costs for the Phase II studies.



Surveillance Studies in [**] Province



c)      Materials and consumables



[**] will clearly need support for all the consumables required for this
project as outlined in the application. This has been estimated from similar
previous studies in Viet Nam.



d)      Equipment



The collaboration with [**] is clearly critical to this application and will
require regular visits to maintain the links. The project will need regular
and reliable transport to [**]. We have requested the support for a 4-wheel
drive vehicle plus petrol, insurance and driver costs that will allow regular
access.



The only reliable way to get around [**] Province to follow up individuals and
families recruited into this project is via motorbike. Many of the subjects
will live well off the main roads and there is no access by car. [**] but
it is not well equipped. [**]. This investment in basic laboratory
infrastructure is essential to ensure the highest yield from the blood culture
and hence the success of this project.



The project will need to invest in computers and communications both in [**].


 








77









 









			
	Q24	 	Reasons for support requested (continued)





     On this page justify (d) Miscellaneous costs requested






Miscellaneous costs requested



Administrative and office costs are required both in [**].



This is a multiparty project with collaborators in the UK, [**], and two
centres in Viet Nam. It is important that there is regular exchange of
information by e-mail and the internet but also intermittent face-to-face
meetings to ensure full exchange of information.


 







78









 








	Q24	 	 Reasons for support requested (continued)
	 
	 	 	On this page justify (e) Use of animals. Address the following:






	 	(i)	 	Why is animal use necessary? Are there any other possible approaches?
	 
	 	(ii)	 	Is the species to be used the most appropriate? This is especially important
when an animal is being used as a model for a human physiological or pathological
condition. Also consider whether the model is an appropriate pharmaceutical industry
standard for the investigation.
	 
	 	(iii)	 	Is the number of animals required to achieve significance in the experimental
design appropriate? What are the factors that might affect this? Outline the sample
size calculations that have been used to estimate the number of animals required in the
proposed experimental design.










  N/A











Q25 Requests for animal costs



(a) Animal species




     Indicate species of animal used:



	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	 	 	Year 1	 	 	Year 2	 	 	Year 3	 	 	Year 4	 	 	Year 5	 
	(b) Purchase
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	 
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	Number to be purchased per annum
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	Source of supply and biological quality
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 






79









 






	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	 	 	Year 1	 	 	Year 2	 	 	Year 3	 	 	Year 4	 	 	Year 5	 
	Purchase price per animal
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	 
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	(c) Maintenance
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	 
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	Number of animals to be maintained
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	 
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	 
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	Number of weeks’ maintenance required
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	 
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	 
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	Cost per animal per week
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	 
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	 
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	(d) Experimental procedures
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	 
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	Types of procedure
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	 
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	 
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	 
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	 
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	 
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	 
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	 
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	Cost per procedure(s)
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 











Name of
applicant:












[**]












80









 








Q26 Financial details of support requested: Salaries



(a) Non-clinical research assistants (UK only)




POST 1




	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	Name:
	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	 	 	 	 	 	 	 	 	 	 	 
	Level Required (specify one, two, three or four):	 	 	 	 	 	 	 	 	 	 
	 

	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	Period of funding sought:	 	From:	 	 	 	to:
	 	 	 	 
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	Full-time o      Part-time o      If part-time, state percentage of full time:	 	 	 	%	 	 	 	 
	 

	 	 	 	 	 	 	 	 	 	 	 	 	 	 





POST 2




	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	Name:
	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	 	 	 	 	 	 	 	 	 	 	 
	Level Required (specify one, two, three or four):	 	 	 	 	 	 	 	 	 	 
	 

	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	Period of funding sought:	 	From:	 	 	 	to:
	 	 	 	 
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	Full-time o      Part-time o      If part-time, state percentage of full time:	 	 	 	%	 	 	 	 
	 

	 	 	 	 	 	 	 	 	 	 	 	 	 	 





POST 3




	 	 	 	 	 	 	 	 	 	 	 
	Name:

	 	 	 	Grade:
	 	 	 	Incremental date:	 	 
	 	 	 	 	 	 	 	 	 	 	 
	Start date:

	 	 	 	End date:
	 	 	 	Time spent on grant (%):	 	 
	 	 	 	 	 	 	 	 	 	 	 





	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	 	 	Year 1	 	 	Year 2	 	 	Year 3	 	 	Year 4	 	 	Year 5	 	 	Total	 
	Commencing salary:
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	London Allowance:
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	Employer’s
contributions:
%
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	 
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	Sub total
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 






POST 4




	 	 	 	 	 	 	 	 	 	 	 
	Name:

	 	 	 	Grade:
	 	 	 	Incremental date:	 	 
	 	 	 	 	 	 	 	 	 	 	 
	Start date:

	 	 	 	End date:
	 	 	 	Time spent on grant (%):	 	 
	 	 	 	 	 	 	 	 	 	 	 





	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	 	 	Year 1	 	 	Year 2	 	 	Year 3	 	 	Year 4	 	 	Year 5	 	 	Total	 
	Commencing salary:
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	London Allowance:
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	Employer’s
contributions:
%
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	 
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	Sub total
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 





(c) Principal investigator(s) or coapplicant seeking his/her own salary




POST 5




	 	 	 	 	 	 	 	 	 	 	 
	Name:	 	 	 	 	 	Level (specify one, two, three or four):	 	 
	 	 	 	 	 	 	 	 	 
	Period of funding sought:	 	Start date:	 	 	 	End date:	 	 
	 

	 	 	 	 	 	 
	 	 	 	 





	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	 	 	Year 1	 	 	Year 2	 	 	Year 3	 	 	Year 4	 	 	Year 5	 	 	Total	 
	Commencing salary:
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	London Allowance:
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	Employer’s
contributions:
%
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	 
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	Sub total
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 






81









 






Q26 Financial details of support requested (continued): Other costs



(d) Research expenses (no inflation allowable for years 2-5)




	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	 	 	Year 1	 	 	Year 2	 	 	Year 3	 	 	Year 4	 	 	Year 5	 	 	Total	 
	Materials and
consumables

(Please give brief
description)
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	 
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	 
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	Subtotal
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	Animals
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	Total purchase price:
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	p.a.
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	 
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	 
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	Total maintenance cost:
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	 
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	 
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	Total procedure cost:
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	 
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	 
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	 
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	Subtotal
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	Miscellaneous
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	 
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	 
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	 
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	 
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	 
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	 
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	Subtotal
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	 
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	Total
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	 
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 







82









 








Q26 Financial details of support requested (continued): Other costs





	(e)	 	Equipment and equipment maintenance
	 
	 	 	This page may be duplicated if necessary. Please include costs for access charges and for
equipment maintenance for equipment not being requested elsewhere in this grant application.
	 
	 	 	Give contact details for the University’s Director of Procurement/Head of Purchasing (or equivalent)





	 	 	 	 	 	 	 
	Name:

	 	 	 	Tel:	 	 
	 

	 	 
	 	 	 	 
	Address:

	 	 	 	Fax:	 	 
	 

	 	 
	 	 	 	 
	 

	 	 	 	E-mail:	 	 
	 

	 	 
	 	 	 	 





	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	 	 	 	 	 	 	Preferred	 	 	 	 	 	 	 	 	 	 	 	 	 
	Type of equipment	 	 	 	 	 	manufacturer	 	 	Preferred supplier	 	 	Number	 	 	Cost per	 	 	 	 
	(see notes)	 	Equipment specification	 	 	(if known)	 	 	(if known)	 	 	of items	 	 	Item	 	 	Total cost	 
	 
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	 
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	 
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	 
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	Total:	 	 	 	 






	 	 	 	 	 	 	 	 	 
	Signature:

	 	 	 	Name (in

full):	 	 	 	 
	 

	 	 
	 	 	 	 	 	 
	 

	 	(University Head of Procurement)
	 	 	 	 	 	 





Name of applicant:



Wellcome Trust University Translation Award Application




83









 








          [**]






Q26 FINANCIAL DETAILS OF SUPPORT REQUESTED (CONTINUED):



(F) REQUEST FOR EQUIPMENT MAINTENANCE AND ACCESS CHARGES (SEE GUIDANCE NOTES)




	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	Type of equipment/facility for	 	Original source/duration of funding	 	 	 	 	 	 	 	 	 	 	 	 
	which access, maintenance or	 	(provide Trust grant reference	 	 	 	 	 	 	 	 	 	 	Estimated usage time for applicant and	 
	upgrade is requested	 	number if applicable)	 	 	Date of award	 	 	Date of purchase	 	 	other users	 
	 
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	 
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	 
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	 
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	 
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	 
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	 
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	 
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 




Wellcome Trust University Translation Award Application





84









 









	Q27 	 	SUBJECT CLASSIFICATION
	 
	(A)	 	SYSTEMS AND PROCESSES

Choose one primary classifier (compulsory) and up to three secondary classifiers




(optional).







Primary: Drug and vaccine Development




	 	 	 
	Secondary:

	 	Infection
	 
	 	 
	 

	 	Immune system









	(B)	 	DISEASE

Choose one primary classifier (compulsory) and up to three secondary classifiers




(optional).







Primary: Bacterial




	 	 	 
	Secondary:

	 	Typhoid









	(C)	 	DISCIPLINE

Choose one primary classifier (compulsory) and up to three secondary classifiers (optional).








Primary: Clinical Research




	 	 	 
	Secondary:

	 	Immunology
	 
	 	 
	 

	 	Microbiology








(D) TECHNIQUE

       Choose up to three classifiers (optional).







N/A







(E) OTHER IDENTIFIER

       Choose up to six classifiers (optional).








N/A








	 	 	 	 	 	 	 
	(f)	 	Check relevant subject classification box
	 

	 	Basic
	 	o	 	 
	 

	 	Clinical
	 	þ	 	 
	 

	 	Tropical
	 	o	 	 
	 

	 	Veterinary
	 	o	 	 
	 

	 	Translation
	 	o	 	 





Wellcome Trust University Translation Award Application






85









 








2.2 Revised Gantt Chart: Detailing activities to be performed in relation to the project




[Illegible chart]




86









 





2.3 Updated Objective Schedule







Objective 1



Preparation, conduct and completion of a Phase II clinical trial in Viet Nam in healthy adult volunteers



The clinical programme will involve Vietnamese subjects of a broad age range (approximately 30–5 years) and will be run as a series of age-descending
studies as it will be important to demonstrate that the vaccine is safe when administered to adults and adolescents prior to administering it to children.
Volunteers will be stratified into three different age brackets: adults (18–30 years); older children (10–18 years); young children (5–10 years). The
initial clinical trial will focus on healthy adults.




Clinical Trial synopsis:



The purpose of the study is to evaluate the immunogenicity and safety of [**]S. typhi (Ty2 aroC  ̄ssaV ̄) ZH9 oral typhoid vaccine in approximately [**]
healthy adult volunteers (age 18 – 30 years inclusive) from Viet Nam. The study will be a single centre, single-blind, placebo-controlled, randomised
study. The study schedule is shown in Table 12.1. The study design will be such that there will be two groups of subjects. Group 1 will receive vaccine
and Group 2 will receive placebo.




Table 12.1 Study schedule for study in healthy adult volunteers




	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	Visit	 	Screen	 	1	 	2	 	3	 	4	 	5	 	6
	Day	 	-28 to -2	 	0	 	1	 	7	 	10	 	14	 	28
	[**]
	 	 	[**]	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	[**]
	 	 	[**]	 	 	 	[**]	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	[**]
	 	 	[**]	 	 	 	[**]	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	[**]
	 	 	[**]	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	[**]
	 	 	[**]	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	[**]	 
	[**]
	 	 	[**]	 	 	 	[**]	 	 	 	[**]	 	 	 	[**]	 	 	 	[**]	 	 	 	[**]	 	 	 	[**]	 
	[**]
	 	 	[**]	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	[**]
	 	 	 	 	 	 	[**]	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	[**]
	 	 	 	 	 	 	[**]	 	 	 	 	 	 	 	[**]	 	 	 	 	 	 	 	 	 	 	 	 	 
	[**]
	 	 	 	 	 	 	 	 	 	 	[**]	 	 	 	[**]	 	 	 	[**]	 	 	 	[**]	 	 	 	 	 
	[**]
	 	 	 	 	 	 	[**]	 	 	 	[**]	 	 	 	[**]	 	 	 	[**]	 	 	 	[**]	 	 	 	[**]	 
	[**]
	 	 	 	 	 	 	[**]	 	 	 	[**]	 	 	 	[**]	 	 	 	[**]	 	 	 	[**]	 	 	 	[**]	 
	[**]
	 	 	 	 	 	 	[**]	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	[**]
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	[**]
	 	 	[**]	 	 	 	[**]	 	 	 	 	 	 	 	[**]	 	 	 	 	 	 	 	[**]	 	 	 	[**]	 
	[**]
	 	 	[**]	 	 	 	[**]	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	[**]	 
	[**]
	 	 	[**]	 	 	 	[**]	 	 	 	 	 	 	 	[**]	 	 	 	 	 	 	 	 	 	 	 	 	 
	[**]
	 	 	[**]	 	 	 	[**]	 	 	 	 	 	 	 	[**]	 	 	 	[**]	 	 	 	 	 	 	 	 	 
	[**]
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	[**]
	 	 	 	 	 	 	[**]	 	 	 	 	 	 	 	[**]	 	 	 	 	 	 	 	 	 	 	 	 	 
	[**]
	 	 	 	 	 	 	[**]	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	[**]	 	 	 	[**]	 





Following completion of the screening assessment subjects who satisfy the study entry criteria will be randomised to one of the two treatment groups
and will receive medication on Day 0. Subjects will be split into at least [**] cohorts for dosing. The time between dosing each cohort may be at least
[**] weeks; it may therefore take [**] weeks to complete dosing of all subjects. The size of the cohorts will be governed by the number of [**] samples
that can be processed on one occasion. In each cohort some








87









 








subjects will receive vaccine and some will receive placebo. The vaccine will be a nominal dose of [**] typhoid vaccine
administered in [**] of presentation solution. Placebo will also be administered in [**] of presentation solution. Vaccine will
be prepared in the pharmacy and administered to the subjects within [**] minutes of preparation.



Subjects will return to the investigative site on study Days [**] for assessment of safety and immunogenicity and to provide
blood, urine and stool samples as required. Subjects will record their temperatures on a Diary Card for the first [**] days
following dosing and will return to the clinic for additional visits should they develop fever.



The primary safety endpoints for the study are the proportion of subjects:





	 	•	 	reporting adverse events during the study, particularity a fever of more than [**]° C, attributable
to the study medication.




The secondary safety endpoints are the proportion of subjects:





	 	•	 	withdrawn from the study due to adverse events, including bacteraemia attributed to study
medication.
	 
	 	•	 	demonstrating bacteraemia, attributable to the study medication
	 
	 	•	 	demonstrating persistent faecal shedding ([**]) of
S. typhi (Ty2 aroC ̄ssaV ̄) ZH9, in stools
	 
	 	•	 	with changes in laboratory parameters from Day 0 to post treatment which are considered clinically
significant




As in previous studies in the UK and US, immunogenicity will be assessed by measuring immune responses against S. typhi
lipopolysaccharide (LPS); using the [**] to measure numbers of circulating antibody secreting cells producing anti-LPS IgA, and
an ELISA assay to measure serum lgG response against LPS. Subjects will be considered to have an immune response if they achieve
the following: a [**]. ELISA assays will be performed on frozen serum samples. It is anticipated that data from the pivotal
immunoassays, [**] to detect secretory IgA against LPS and ELISA to detect serum IgG against LPS, will be available for review
within [**] weeks of dosing the first subject.



Once a full dataset is available from safety assessments and from the pivotal immunoassays, the data will be evaluated by
Microscience, the clinical investigators, the regulatory agencies and by the local ethics committee to establish whether it
provides adequate confidence to progress to evaluation of safety and immunogenicity in children.








88











 










Objectives/key tasks/responsibilities:





	 	•	 	Identification of site: Responsibility of the clinical investigators [**]. It
is important that phase II safety and immunogenicity data is generated in subjects
representative of the target population for the field study. It is therefore intended
that a number of the phase II studies will be performed in the endemic region in the
Mekong Delta. However, at least the first study, in adult volunteers, will be
undertaken under well-controlled conditions at the Oxford University Clinical Research
Unit at the Hospital of Tropical Diseases in Ho Chi Minh City. This will ensure that
technology is transferred, staff are trained and the regulatory approval process is
undertaken as efficiently as possible, prior to moving the programme into the endemic
region. Once vaccine safety has been adequately demonstrated in this study approval
will be sought to perform subsequent studies in the endemic region.
	 
	 	•	 	Clinical protocol development: The protocol will be owned by Microscience but
developed jointly by Microscience and the clinical investigators ([**]).
	 
	 	•	 	Regulatory approval: Microscience will be responsible for obtaining regulatory
approval for the clinical study. Approval will be sought from both the Vietnamese and
US regulatory agencies, as it is intended that the clinical programme will be performed
under the existing US IND that is held for this product by Microscience.
	 
	 	•	 	Local ethics approval: The clinical investigators ([**]) will be responsible
for obtaining ethics approval from the local Independent Review Board (IRB).
Microscience and the clinical investigators ([**]) will be responsible for preparing
the documentation required for submission.
	 
	 	•	 	Assay transfer: Assay transfer from Microscience to the Hospital for Tropical
Diseases is the responsibility of both parties and is expected to take 1 month. The
immunoassays being used for these studies have been standardised at Microscience.
Assay transfer will ensure that assay performance is comparable at the Hospital for
Tropical Diseases, at Microscience and in previous clinical studies. The process
involves performing the assays multiple times using reference samples. Transfer will
be considered successful once an analyst has performed a pre-defined number of assays
that have each met the validity criteria.
	 
	 	•	 	Manufacture and release of clinical material: Responsibility of Microscience.
The clinical material will be vaccine, placebo and [**], manufactured to cGMP. [**]








89












 











It is anticipated that existing batches of vaccine, placebo and [**] will be
used for the adult study; only packaging and labelling will be required for this
study. Following review of packaging and labelling batch records and receipt of
regulatory and ethics approval, the material will be released by Microscience
for use in the clinic.




	 	•	 	Screening and recruitment of subjects: Responsibility of the clinical
investigators ([**]). To begin once regulatory and ethics approval have been obtained.
For each subject screening has to occur within 28 days of dosing. All efforts will be
put in place to obtain written consent that is informed and given voluntarily as
described in Appendix C.
	 
	 	•	 	Dosing: Responsibility of the clinical investigators ([**])
	 
	 	•	 	Evaluation of safety: Responsibility of the clinical investigators ([**]).
	 
	 	•	 	Completion of immunoassays: Responsibility of the clinical investigators
([**]).
	 
	 	•	 	Monitoring of study (safety and GCP): Responsibility of Microscience.
	 
	 	•	 	Management and validation of data: Responsibility of Microscience.
	 











90









 










Objective 2



Preparation, conduct and completion of two Phase II clinical trials to demonstrate safety,
tolerability and immunogenicity in Vietnamese adolescents and children living in an endemic
region



Following completion of the adult study in a non-endemic region, this section of the
programme will involve a series of age-descending studies. The purpose is to evaluate safety
and immunogenicity of the vaccine in children and adolescents from 5-18 years. Approximately
[**] children will be involved, stratified into two age groups: 10–18 years, approximately
[**] subjects; 5–10 years, approximately [**] subjects. The vaccine will be administered
initially to adolescents and then to children. These studies will be conducted in the
endemic area that will be selected as a potential site for the phase III efficacy study.



The studies will be single centre, single-blind, placebo-controlled, randomised studies. The
basic study schedules will be as for the adult study shown in Table 12.1.




Objectives/key tasks for each study





	 	•	 	New batches of vaccine and placebo will be manufactured in 2005 for the studies
in children. Following packaging and labelling, review of the manufacturing batch
records and receipt of regulatory and ethics approval, the material will be released by
Microscience for use in the clinic.
	 
	 	•	 	Dosing. Responsibility of the clinical investigators ([**]).
Group 10–18 years — it is anticipated that data from the adult study will support
the use of the same dose level, [**] nominal dose, and formulation of vaccine as
was administered to adults.
	 
	 	 	 	
Group 5-10 years – evaluation of safety data from the study in 10-18 year olds
will determine whether dose escalation will be required for this study. Dose
escalation will require and additional group of subjects who will receive a lower
vaccine dose level (likely to be [**]).
	 
	 	•	 	Evaluation of safety. Responsibility of the clinical investigators ([**]).
As for adult study.
	 
	 	•	 	Completion of immunoassays. Responsibility of the clinical investigators
([**]).
The assays used will be the same as for the adult study.
	 
	 	•	 	Monitoring of study (safety and GCP). Responsibility of Microscience.
	 
	 	•	 	Management and validation of data. Responsibility of Microscience.




Once a full dataset is available from safety assessments and from the pivotal immunoassays,
the data will be evaluated to establish whether it is adequate to support entry of children
into the phase III field study.









91









 












Objective 3



Preparation of field site for Phase III study



The activities listed below, necessary for the completion of Objective 3, will not commence until adequate funding of
the phase III clinical development programme has been secured, likely either through a commercial collaboration with a
pharmaceutical partner or through an NGO collaboration.




Objectives/key tasks





• Identification of site. [**] will have joint responsibility.
The decision as to which area will be the site for the efficacy study and therefore for surveillance will be based
on known levels of incidence as defined by current government statistics, predicted levels of incidence and the
ease with which the required infrastructure can be put in place. The site will be in the Mekong Delta region of
Viet Nam. This area has been chosen because population based surveillance studies for typhoid fever have
previously been carried out in this region in 1995/1996. (8) It was found that the incidence level was high
(overall it was 198 per 105 of the general population). The highest attack rate was among the 5-9 year
olds and lowest in the >30 year olds. It was concluded from these studies that typhoid fever is highly endemic
in Viet Nam and is a significant disease in both pre-school and school aged children. A region in the Mekong
Delta ([**]) has been selected for this proposal.




A typhoid surveillance study will be conducted in the proposed field-site and data will be collected for at least
one year prior to phase III immunication commencing and will continue throughout the duration of the efficacy
study. The end-point of the pre-study surveillance will be a rate of incidence of typhoid fever in the study
population. These data will be used to determine the number of subjects to be entered into the phase III efficacy
study.




	 	•	 	Establishment of infrastructure. [**] will have joint responsibility.
	 
	 	•	 	Perform Census. [**] will have joint responsibility.






	 	 	 	A census will be performed in the study area. [**]. Each of these households and each individual residing in the
household is given a unique identification number (ID#), which is used for all interactions that occur as part of
the study. ID numbers will be allocated based on the serial number of the census form, and the sequential order
within each household. The aims of the census will be as follows:






	 	•	 	To assign a unique study number to each household
	 
	 	•	 	To assign a unique study identification number to each individual resident in the
household
	 
	 	•	 	To obtain base-line data on socio-economic status, health seeking behaviour, prior
typhoid vaccine usage and potential typhoid risk factors
	 
	 	•	 	To provide the household members with information on the project






	 	•	 	Establish and provide training in diagnostic tools. [**] will have joint responsibility.









92









 








         •          
Disease surveillance. [**] will have joint
responsibility.


The surveillance system will rely on patients attending existing healthcare
facilities in the endemic region (government health care facilities and
participating private healthcare physicians). This healthcare
facility-basedpassive surveillance system will be aimed at detecting the
majority of reported cases of typhoid fever among study participants seeking
medical care. Medical personnel will interview, examine, and obtain a venous
blood specimen for laboratory investigation from all patients living in the
study area with [**].



All relevant clinical information will be recorded using standard procedures
and will include; date and time of examination; name; study ID number; age and
gender; full address; name of head of household; number of days since disease
began; symptoms and signs of the disease. The venous blood sample will be
taken to identify the presence of S. typhi by blood culture. Serum will also
be taken for typhoid fever serological assays.



Typhoid fever proven cases will be given antibiotic treatment as appropriate.
It is anticipated that S. typhi resistance patterns will be monitored regularly
throughout the study.



A crucial feature of the surveillance programme will be the accurate
identification of all patients attending healthcare facilities, who are study
participants. To accomplish this, each clinical supervisor will attempt to
identify patient ID numbers using a computer search programme (for names, age
ranges, dates of birth, sex, names of the head of households).



Additionally, all culture-proven cases and positive serological cases will be
visited at home to confirm the identification of the patient; to assess
clinical progress; to assess any typhoid fever-related disability; to determine
typhoid carrier status and to apply a verbal autopsy when needed.



Culture-proven typhoid fever cases will be visited [**] after onset of illness.
Follow-up questionnaires will be completed at each visit. Stool samples will
also be collected at the end of the post-immunization [**] year follow-up on
all typhoid fever cases during a home visit, with the aim of identifying
typhoid carriers.








93









 








2.4 Updated Budget




Appendix F

Summary of Costs




	 	 	 	 	 	 	 	 	 
	 	 	US $	 	GB £*
	Phase II clinical studies Viet Nam
	 	 	[**]	 	 	 	[**]	 
	 
	Personnel costs (research fellow, data manager)
	 	 	[**]	 	 	 	[**]	 
	 
	Manufacturing costs
	 	 	[**]	 	 	 	[**]	 
	 
	Surveillance
	 	 	[**]	 	 	 	[**]	 
	 
	Microscience resource costs
	 	 	[**]	 	 	 	[**]	 
	 
	*Exchange Rate 1GBP = 1.65US$
	 	 	 	 	 	 	 	 
	 
	TOTAL
	 	 	[**]	 	 	 	[**]	 






Objective 1:




     Preparation, conduct and completion of phase II adult study in Ho Chi Minh City



Objective 2:




     Preparation, conduct and completion of phase II adolescent and children’s studies in endemic area

     Manufacturing additional phase II clinical trial material for adolescent and children’s
studies



Objective 3:




Preparation of field site for phase III study

     Start of objective 3 activities flexible, dependent on partnering / further NGO funding




94









 








Schedule 3




Background Intellectual Property



Background Intellectual Property – some of the Background Intellectual Property is jointly owned
with Imperial College Innovations Limited but, as between Imperial College Innovations Limited and
Microscience Limited, Microscience Limited has the sole right to grant further licences of such
Background Intellectual Property





	1.	 	“Identification of Genes” 

Patent application WO 96/17951
	 
	2.	 	“Attenuated Microorganisms for the Treatment of Infection” 

Patent Application WO 00/68261




The Background Intellectual Property is subject to the following Encumbrances:





	1.	 	A loan note facility dated 6th October 2004 provided by the existing
investment syndicate to Microscience to fund the working capital requirements of the group
pending agreement of a series C financing round; and
	 
	2.	 	Fixed and floating charges over all Microscience assets, including the rights and
benefits of this Agreement, in favour of the holders of loan notes to secure loan notes
provided under a loan note agreement dated 6th October 2004.




95









 











Schedule 4

Microscience Territory



Australia



New Zealand



Canada



European Union (including any new member states that join the European Union while this Agreement
is in force, provided that if any such new member state of the European Union has become part of
the Trust Territory by virtue of the provisions of Clause 10 before it becomes part of the European
Union, that member state shall not become part of the Microscience Territory)



European Free Trade Area (EFTA)



Japan



Norway



United States of America




96









 








Schedule 5




Microscience Option Territory




All countries, dominions, protectorates, colonies and other territories of the

world not set out in Schedule 4.




97









 





Schedule 6

Press Release and Statement




	 	 	 	 	 
	A

	 	Microscience Press Release
	 	 






Microscience PLC




Wellcome Trust makes £1.95 Million Programme Related Investment to Advance

Microscience’s Phase II Typhoid Vaccine Programme in South East Asia



Wokingham, UK, [Date]: Microscience PLC announces that it has been awarded a Wellcome Trust
Strategic Translation Award (STA) of £1.95 million to advance the clinical development of
Microscience’s drinkable typhoid vaccine programme. This is the largest single STA ever made by
the Wellcome Trust.



Wellcome Trust STAs aim to provide vital financial bridging for important healthcare programmes and
are awarded to researchers in fields of strategic importance to the Wellcome Trust and that address
major unmet healthcare needs. The Microscience single-dose drinkable vaccine targets a significant
medical need for both travellers to typhoid-endemic areas and the endemic population in large areas
of the developing world.



Beginning in early 2005, Microscience, with this financial support from the Wellcome Trust, will
undertake the next stage of the Phase II clinical development programme of its oral typhoid
vaccine, set up a surveillance programme to determine demographics and disease prevalence in the
region and prepare the field-site for the Phase III efficacy study. As the incidence of disease in
typhoid endemic regions tends to be the most prevalent in children, this population will form a key
element of the Phase III efficacy study.



The programme will be undertaken in conjunction with the Hospital for Tropical Diseases in Ho Chi
Minh City, Viet Nam and Oxford University, UK. This long-standing collaboration focusing on
infectious diseases important in Viet Nam has been funded by the Wellcome Trust since 1991.



The first study will evaluate safety and immunogenicity in adult volunteers in a controlled setting
in Ho Chi Minh City and is planned to commence during the first half of 2005. Following the
completion of this study, a series of age-descending Phase II studies will be carried out prior to
the large-scale Phase III field study.



Previous trials with this drinkable vaccine in over 100 subjects in the US and UK showed it to be
highly immunogenic at a single dose with a good safety profile.



Rod Richards, Chief Executive Officer of Microscience, commented:




98









 







“The sizeable grant awarded to Microscience by the Wellcome Trust is a clear recognition of the
need for a new and effective typhoid vaccine and a significant endorsement of our proprietary
approach. The STA investment and collaboration gives us the momentum needed to move into
large-scale field studies. It will enable us to pursue a clear path to commercialisation for our
typhoid vaccine, with the potential to address healthcare needs to both tourists and business
travellers from Europe and North America as well as the needs of the developing world.”



Dr. Jeremy Farrar, Director of the Oxford University-Wellcome Trust Clinical Research Unit in Viet
Nam, said: “Typhoid is almost untreatable in parts of Viet Nam because of drug resistance.
Therefore an easy-to-use vaccine like this could be of tremendous value in preventing infection in
parts of the world where typhoid remains such an important disease.”



Dr Ted Bianco, Director of the Wellcome Trust’s Technology Transfer Division said: “Our ultimate
goal is to translate research into better healthcare and to facilitate the dissemination of new
technologies to maximise the benefit to society globally. This vaccine trial is an excellent
example of how we can assist in the development of a promising new product with a view to exploring
its usefulness in areas beyond the main commercial markets but where the disease is a particular
problem.”




- Ends -




Enquiries:




	 	 	 
	Microscience

	 	+ 44 (0)118 944 3300
	 
	 	 
	Rod Richards, Chief Executive Officer
	 	 
	 
	 	 
	Weber Shandwick Square Mile

	 	+ 44 (0)20 7067 0700





Sarah MacLeod / Yvonne Alexander




Notes to Editors



About Typhoid



Typhoid is caused by the Salmonella typhi bacterium and is transmitted via contaminated drinking
water or food. Infection typically causes sustained fever, headache, constipation,


99









 






malaise, stomach pains, anorexia and myalgia. In severe cases, patients experience confusion,
delirium and intestinal perforation, leading to death in some cases.



According to World Health Organisation estimates, between 17 to 33 million cases of typhoid fever
occur annually worldwide. The infection results in approximately 400 travellers returning to the
US each year having contracted the disease abroad and in approximately 600,000 deaths annually
worldwide, of which 70% occur in Asia.




Current Treatment



Antibiotics are used to treat the disease and usually lead to recovery commencing within four days.
Without antibiotic therapy, the mortality rate is up to 30 per cent. In recent years, strains
exhibiting resistance to some of the antibiotics have emerged, driving demand for an effective
prophylactic vaccine for travellers to “high-risk” areas. There are currently injectible vaccines
available however, there is an unmet need and significant opportunity for an efficacious oral,
single dose vaccine that would prevent the need for injection.




Microscience Drinkable Typhoid Vaccine



The advent of modern molecular biology techniques has led to the identification of several genes
that are essential for the in vivo growth and survival of the organism. This has provided new gene
targets for attenuation, leading to the concept that introducing defined non-reverting mutations
into selected genes known to be involved in virulence can ‘rationally’ attenuate future vaccine
strains. This has facilitated the development of improved vaccines, particularly in terms of
increasing the immunogenicity and therefore reducing the number of doses that have to be
administered.



Microscience’s new single-dose, drinkable, typhoid vaccine contains independently attenuating
deletions in two genes, aroC and ssaV. The aroC gene encodes chorismate synthase, an enzyme
involved in the biosynthesis of aromatic compounds, aro mutations are well described as being
attenuating for Salmonella in humans. The ssaV gene is encoded on Salmonella Pathogenicity Island
2 (SPI-2). SPI-2 encodes a type III secretion system and ssaV is a structural gene encoding part
of the secretion apparatus. The deletion of the ssaV gene prevents the bacteria replicating inside
the antigen presenting cell.



The Microscience vaccine stimulates not only a systemic antibody response but also unlike
injectible typhoid vaccines stimulates an immune response at the mucosal surface in the gut. This
is important as this is the first line of defence following exposure to typhoid.




Clinical Development to Date



To date, three clinical studies involving over 100 healthy adult volunteers have been conducted.
These studies showed the vaccine to be highly immunogenic, generating both systemic and mucosal
responses, at a single dose with a good safety profile. In trials it has been administered in a
presentation suitable for commercialisation.




100









 








Strategic Translation Awards (STAs)



The WT seek collaborations with industry or academia that can achieve commercialization of new
technologies and products. Technology Transfer at the Wellcome Trust proactively seek applications
from development scientists conducting research in strategic areas who wish to work in partnership
with the Trust to achieve the commercial translation of targeted technologies. Collaborating
researchers benefit from access to the Wellcome Trust’s considerable expertise and networks.




	 	 	 	 	 
	B
	 	Trust Statement
	 	 





The safety and immunogenicity of a single dose oral typhoid vaccine in Vietnamese healthy
adults and children and identification and preparation of a field site for a Phase III efficacy
study.



Typhoid fever remains a major disease of the developing world. There is currently no available
affordable vaccine that offers long-term protection after a single dose. Microscience aims to
clinically evaluate their vaccine, already tested in studies in the UK and US, in healthy
Vietnamese adults and children. In conjunction with the Wellcome Trust programme led by Dr Jeremy
Farrar in Vietnam, it is also planned to set up a field site in the Mekong Delta region where
future phase II and III studies can be carried out to assess whether the vaccine protects against
typhoid fever following natural exposure.





101









 







Page 1 of 4




DATED June 24, 2005




THE WELLCOME TRUST LIMITED




MICROSCIENCE HOLDINGS PLC




and



MICROSCIENCE LIMITED




 






DEED OF ASSIGNMENT AND NOVATION




relating to




INVESTMENT AGREEMENT RELATING TO




MICROSCIENCE HOLDINGS PLC




 






(logo)

Pinsent Masons




 









 





Page 2 of 4



THIS DEED OF NOVATION is made on June 24 2005




BETWEEN





	1.	 	THE WELLCOME TRUST LIMITED a company incorporated in England and Wales under registration
number 2711000 whose registered office is at 215 Euston Road, London NW1 2BE, as trustee of
the Wellcome Trust, a charity registered in England under number 210813 (the “Trust”);
	 
	2.	 	MICROSCIENCE HOLDINGS PLC a company incorporated in England and Wales under registration
number 5106930 whose registered office is at 545 Eskdale Road, Winnersh, Wokingham, Berkshire
RG41 5TU (“MS Holdings”); and
	 
	3.	 	MICROSCIENCE LIMITED a company incorporated in England and Wales under registration number
3270465 whose registered office is at 545 Eskdale Road, Winnersh, Wokingham, Berkshire RG41
5TU (“MS Limited”);
	 
	 	 	together the “Parties”.





WHEREAS:





	A.	 	By an agreement (the “Agreement”) dated 18 March 2005 between the Parties, the Trust agreed,
inter alia, to make a Programme Related Investment (as defined in the Agreement) by way of
subscribing for ordinary shares in MS Holdings and providing further funding to MS Holdings to
undertake research and development of MS Holdings’ single-dose, oral type typhoid vaccine.
	 
	B.	 	MS Holdings has agreed to sell its shareholding in MS Limited to a subsidiary of Emergent
Biosolutions, Inc. which will mean that MS Holdings is unable to perform its obligations under
the Agreement.
	 
	C.	 	In contemplation of the completion of the transaction set out in recital B, MS Holdings has
agreed to assign to MS Limited the benefit of the Agreement, subject to the consent of such
assignment by the Trust.
	 
	D.	 	Following the completion of the sale of the shares in MS Limited by MS Holdings
(“Completion”), MS Limited wishes to perform the Agreement and (subject to this Deed) MS
Limited and the Trust have agreed to release MS Holdings from its obligations under the
Agreement on and with effect from Completion and the Parties have agreed that with effect from
such date the rights and obligations of MS Holdings in relation to the Agreement shall be
novated to and assumed by MS Limited in its own right and on its own behalf in substitution
for MS Holdings.





NOW THIS DEED witnesses as follows:





	1.	 	Assignment by MS Holdings
	 
	1.1	 	MS Holdings assigns to MS Limited with full title guarantee the rights, claims, liberties and
full benefit of the Agreement to hold the same unto MS Limited absolutely.
	 
	1.2	 	At the request and cost of MS Limited, MS Holdings shall, at all times after the date of this
deed, do all acts and execute all documents as may be reasonably necessary or desirable to
secure the vesting in MS Limited of the benefit of the Agreement.
	 
	1.3	 	The Trust hereby consents to the assignment of the Agreement pursuant to this Clause, and the
restriction on assignment contained in clause 20.1 of the Agreement is hereby waived in
respect of such assignment.




 









 





Page 3 of 4










	2.	 	Undertaking by MS Limited
	 
	 	 	Subject to Clause 6, on and with effect from the date of Completion, MS Limited
undertakes with the Trust and MS Holdings to perform and accept all obligations and
liabilities arising under the Agreement on and with effect from Completion and to be
bound by the terms of the Agreement in every way as if MS Limited were named therein in
place of MS Holdings.
	 
	3.	 	Release of MS Holdings
	 
	 	 	Subject to Clause 6, on and with effect from the date of Completion, the Trust releases
and discharges MS Holdings from all obligations, claims, liabilities and demands
whatever arising under the Agreement on or after the date of Completion and accepts the
liability of MS Limited under the Agreement in place of the liability of MS Holdings
and agrees to be bound by the terms of the Agreement in every way as if MS Limited was
named therein in place of MS Holdings.
	 
	4.	 	Intellectual Property Assignment
	 
	 	 	On and with effect from the date of Completion, MS Holdings hereby assigns with full
title guarantee all its rights title and interest in the Project Intellectual Property
(as defined in the Agreement) and the Background Intellectual Property (as defined in
the Agreement) to MS Limited.
	 
	5.	 	Consequential Amendments
	 
	 	 	Subject to Clause 6, on and with effect from the date of Completion, as between the
Trust and MS Limited and to the extent relevant for the purposes of carrying out their
obligations under the Agreement all references in the Agreement to MS Holdings shall
with respect to the rights and obligations arising on or after the date of this
novation be deemed to be references to MS Limited and all other necessary amendments
consequent upon the change of identity of the parties shall be deemed to be made in the
Agreement.
	 
	6.	 	Variation of clause 8 of the Agreement
	 
	6.1	 	The amount of £[**] of the First Instalment paid to MS Holdings by the Trust shall be treated
as a subscription by the Trust for an additional [**] A ordinary shares in the capital of MS
Holdings and accordingly the figure in clause 8.1 of the Agreement of “[**]” shall be and is
hereby deleted and replaced with the figure of “[**]” and clause 8.2 of the Agreement shall be
deleted and left blank.
	 
	6.2	 	MS Holdings will immediately issue and allot to the Trust fully paid an additional [**] A
ordinary shares.
	 
	7.	 	Extent of Novation
	 
	 	 	Nothing in this deed:






	 	(a)	 	shall impose on MS Limited any obligations other than those contained
in the Agreement or any liability to issue equity to the Trust; or
	 
	 	(b)	 	relieve MS Holdings from any obligations other than those contained
in the Agreement.




 









 






Page 4 of 4











	8.	 	Governing law and jurisdiction
	 
	8.1	 	This deed and any disputes or claims arising out or in connection with its subject matter are
governed by and construed in accordance with the laws of England.
	 
	8.2	 	The parties irrevocably agree that the courts of England have exclusive jurisdiction to
settle any dispute or claim that arises out of or in connection with this deed.




IN WITNESS WHEREOF the Parties hereto have executed and delivered this document as a deed the day
and year first above written.




	 	 	 	 	 	 	 	 	 
	EXECUTED AS A DEED by
THE WELLCOME 
TRUST LIMITED as

trustee of the WELLCOME
TRUST acting by

	 	 	)

)

)	 	 	  /s/  [Illegible]
	 	  /s/  [Illegible]
	 

	 	 	 	 	 	 
	 	 
	 

	 	 	 	 	 	Authorised

Signatory
	 	Authorised

Signatory
	 
	 	 	 	 	 	 	 	 
	EXECUTED AS A DEED by
MICROSCIENCE 
HOLDINGS PLC
acting by:

	 	 	)

)	 	 	  /s/  [Illegible]
	 	  /s/  [Illegible]
	 

	 	 	 	 	 	 
	 	 
	 

	 	 	 	 	 	Director/Secretary
	 	Director
	 
	 	 	 	 	 	 	 	 
	EXECUTED AS A DEED by MICROSCIENCE 
LIMITED 

	 	 	)	 	 	 	 	 
	
 acting by:

	 	 	)	 	 	  /s/  [Illegible]
	 	   /s/  [Illegible]
	 

	 	 	 	 	 	 
	 	 
	 

	 	 	 	 	 	Director/Secretary
	 	Director