Safety and Immunogenicity of Anti-Pneumococcal Vaccines in HIV-Infected Pregnant Women
Phase: PHASE2
Conditions: PNC Vaccine, HIV-infected Pregnant Women
Sponsor: Westat

NICHD P1091 
VERSION 2.0 
FINAL 
May 23, 2016 
 
Page 1 of 93 
 
 
 
Version 2.0 
May 23, 2016 
Safety and Immunogenicity of Anti-Pneumococcal  
Vaccines in HIV-Infected Pregnant Women: NICHD P1091 
Sponsored by: 
The Eunice Kennedy Shriver  
National Institute of Child Health and Human Development (NICHD) 
Protocol Chair(s): 
Adriana Weinberg, M.D. 
 
Marisa Mussi, M.D. 
 
Geraldo Duarte, M.D. 
 
NICHD Medical Officer: 
Nahida Chakhtoura, M.D. 
 
Protocol Specialist:  
Lauren Laimon, M.S. 
 
 

NICHD P1091 
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May 23, 2016 
 
Page 2 of 93 
Table of Contents 
Chapter 
Page 
 
P1091 Protocol Team Roster .................................................................  
6 
 
NICHD P1091 Roster ............................................................................  
7 
 
NICHD International Site Roster ...........................................................  
10 
 
List of Commonly Used Abbreviations .................................................  
12 
 
Schema ...................................................................................................  
15 
 
1.0 
Introduction ............................................................................................  
17 
 
1.1 
Background ................................................................................  
17 
1.2 
Significance................................................................................  
28 
 
2.0 
Study Objectives ....................................................................................  
29 
 
2.1 
Primary Objectives.....................................................................  
29 
2.2 
Secondary Objectives.................................................................  
29 
2.3 
Tertiary Objectives.....................................................................  
29 
 
3.0 
Study Design ..........................................................................................  
31 
 
4.0 
Selection and Enrollment of Participants ...............................................  
32 
 
4.1 
Step 1 – Inclusion Criteria for Pregnant Women .......................  
32 
4.2 
Step 1 – Exclusion Criteria for Pregnant Women ......................  
33 
4.3 
Step 2 – Inclusion Criteria for Women ......................................  
34 
4.4 
Step 2 – Exclusion Criteria for Women .....................................  
34 
4.5 
Step 3 – Inclusion Criteria for Women ......................................  
35 
4.6 
Step 3 – Exclusion Criteria for Women .....................................  
35 
4.7 
Concomitant Medication Guidelines .........................................  
36 
4.8 
Enrollment Procedures ...............................................................  
36 
4.9 
Co-enrollment Procedures .........................................................  
37 
4.10 
PPV-23 and PCV-10 Availability at Participating Sites ............  
37 
 
 
 

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Contents (continued) 
Chapter 
Page 
 
5.0 
Study Treatment .....................................................................................  
38 
 
5.1 
Drug Regimens, Administration and Duration ..........................  
38 
5.2 
Study Product Formulation ........................................................  
39 
5.3 
Pharmacy Procedures .................................................................  
39 
 
6.0 
Participant Management and Adverse Event Reporting ........................  
41 
 
6.1 
Definitions..................................................................................  
41 
6.2 
Toxicity Management ................................................................  
42 
6.3 
Participant Management ............................................................  
43 
6.4 
Criteria for Treatment Discontinuation ......................................  
45 
6.5 
Criteria for Study Discontinuation .............................................  
45 
6.6  
Study Results .............................................................................  
45 
 
7.0 
Expedited Adverse Event Reporting ......................................................  
46 
 
7.1 
Reporting Requirements ............................................................  
46 
7.2 
Recording of Adverse Events requiring Expedited 
Reporting....................................................................................  
47 
7.3 
Grading Severity of Adverse Events..........................................  
47 
7.4 
Relationship to Study Products ..................................................  
47 
7.5 
Expedited Adverse Event Reporting Category ..........................  
48 
7.6 
Adverse Event Reporting Period ...............................................  
48 
7.7 
Follow-up Expedited Adverse Event Report .............................  
48 
 
8.0 
Statistical Considerations .......................................................................  
49 
 
8.1 
General Design Issues ................................................................  
49 
8.2 
Outcome Measures.....................................................................  
49 
8.3 
Randomization and Stratification ..............................................  
51 
8.4 
Sample Size and Accrual ...........................................................  
51 
8.5 
Monitoring .................................................................................  
53 
8.6 
Analyses .....................................................................................  
54 
 
9.0 
Human Subjects .....................................................................................  
59 
 
9.1 
Institutional Review Board and Informed Consent ...................  
59 
9.2 
Participant Confidentiality .........................................................  
59 
9.3 
Study Discontinuation ................................................................  
60 

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Contents (continued) 
Chapter 
Page 
 
10.0 
Publication of Research Findings ..........................................................  
61 
 
11.0 
Biohazard Containment .........................................................................  
62 
 
12.0 
References ..............................................................................................  
63 
 
 
Appendixes 
 
I 
Maternal Schedule of Evaluations .........................................................  
72 
 
II 
Infant Schedule of Evaluations ..............................................................  
74 
 
III 
P1091 Protocol Testing Laboratories.....................................................  
75  
 
IV 
Instructions for Nasopharyngeal (NP) and Oropharyngeal (OP) 
Sample Collection ..................................................................................  
76 
 
V 
Study Participant Information Sheet ......................................................  
77 
 
VI 
Home Record/Diary Card for P1091 .....................................................  
78 
 
VII 
Sample Informed Consent......................................................................  
80 
 
 
Tables 
 
1-1 
Reports of PPV-23 safety and/or immunogenicity in pregnancy ..........  
21 
 
8-1 
Maternal response: sample sizes needed to provide 80 percent 
statistical power to detect differences in response rate as a 
function of PPV-23 versus PCV-10. ......................................................  
52 
 
8-2 
Infant rate of protective antibody titers: sample sizes needed to 
provide 80 percent statistical power to detect differences in 
protective rate as a function of PPV-23 versus PCV-10 ........................  
52 
 
8-3 
90 percent confidence intervals around potential rates of 
grade ≥ 3 AEs within any of the treatment groups (N = 115) ................  
55 
 
 
 

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Contents (continued) 
Tables 
Page 
 
8-4 
Statistical power for pairwise comparisons between either of 
the vaccine groups and the placebo group with respect to the 
proportions of participants with grade ≥ 3 AEs. (1-tailed 
Fisher’s exact tests of vaccine > placebo, alpha=.05) ............................  
55 
 
 
 

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P1091 Protocol Team Roster 
All questions concerning this protocol should be sent via email to nichd.teamp1091@fstrf.org. 
Remember to include the participant identification number (PID) when applicable. The 
appropriate team member will respond to questions via email with a “cc” to 
nichd.teamp1091@fstrf.org. A response should generally be received within 24 hours (Monday – 
Friday).  
 
Brazil Sites 
For protocol registration questions, email Regulatory@westat.com or call 1-888-464-5246 (toll-
free) or 00 1 240-453-5661 (long distance charges). Protocol registration material can be sent 
electronically to Regulatory@westat.com or via fax at 1-888-865-1983 or 00 1 240-455-5580 
(long distance charges).  
 
For Adverse Event (AE) questions, email Regulatory@westat.com or call 1-888-464-5246 (toll-
free) or 00 1 240-453-5661 (long distance charges) or fax at 1-888-865-1983 or 00 1 240-455-
5580 (long distance charges). 
 
For information on ordering study products, please refer to the NICHD P1091 Manual of 
Procedures (MOP). For randomization or enrollment questions, contact the Data Management 
Center (DMC) at 716-834-0900 or by email at rando.support@fstrf.org.   
 
 
 

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NICHD P1091 Roster 
Protocol Chair 
Adriana Weinberg, M.D. 
University of Colorado Denver 
Mail Stop 8604 
12700 E. 19th Avenue, Room 11126 
Aurora, CO 80045 
Phone: 303-724-4480 
Email: adriana.weinberg@ucdenver.edu  
Protocol Chair 
Marisa Mussi, M.D. 
University of Sao Paulo Brazil 
Ribeirão Preto Medical School Av. 
Bandeirantes 3900 
Ribeirão Preto 
Sao Paulo 
CEP 14049-900 
Brazil 
Phone: 55-16-3602-2807 
Email: mmmpinha@fmrp.usp.br  
 
Protocol Chair 
Geraldo Duarte, M.D. 
University of Sao Paulo Brazil 
Ribeirão Preto Medical School Av. 
Bandeirantes 3900 
Ribeirão Preto 
Sao Paulo 
CEP 14049-900  
Brazil 
Phone: 55-16-3602-2588 
Email: gduarte@fmrp.usp.br 
 
NICHD Medical Officer 
Nahida Chakhtoura, M.D. 
Eunice Kennedy Shriver National Institute of  
Child Health and Human Development 
Maternal and Pediatric Infectious Disease  
Branch 
6100 Executive Boulevard, Room 4B11G 
Bethesda, MD 20892 
Phone: 301-435-6872 
Email: nahida.chakhtoura@nih.gov 
 
Contracting Officer Representative 
Eric Lorenzo 
Eunice Kennedy Shriver National Institute of  
Child Health and Human Development 
Maternal and Pediatric Infectious Disease  
Branch 
6100 Executive Boulevard, Room 4B11G 
Bethesda, MD 20892 
Phone: 301-443-4993 
Email: eric.lorenzo@nih.gov 
 
Protocol Specialist 
Lauren Laimon, M.S. 
Westat 
1600 Research Boulevard 
Rockville, MD 20850 
Phone: 240-453-2987 
Email: laurenlaimon@westat.com 
 
 

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NICHD P1091 Roster (continued) 
 
Clinical Research Associate/Pharmacist 
Adriana Ferreira, PharmD, M.B.A., C.C.R.A. 
Westat 
Estrada do Guanumbi 138  
Rio de Janeiro  
CEP 22745-200 
Brazil  
Phone: 55-21-3174-6470 
Email: adrianaferreira@westat.com 
Pharmacist 
Julio César Gabaldi 
Ribeirão Preto Medical School  
University of Sao Paulo, Brazil 
Avenue Bandeirantes 3900 
Ribeirão Preto 
São Paulo 
CEP 14049-900 
Brazil 
Phone: 55-16-3602-2760 
Email: juliohcrp@yahoo.com.br  
 
Laboratory Investigator 
Stephen Ira Pelton, M.D. 
Boston University School of Medicine 
Boston Medical Center 
774 Albany Street, Room 512 
Boston, MA 02118 
Phone: 617-414-7407 
Email: spelton@bu.edu 
Laboratory Investigator 
David Goldblatt, MB.Ch., Ph.D., F.R.C.P.,  
F.R.C.P.C.H.   
Great Ormond Street Hospital (GOSH)   
Immunobiology 
Institute of Child Health, University College  
London (UCL) 
30 Guilford Street 
London WC1N 1EH 
Phone: 020-7905-2215 
Email: d.goldblatt@ucl.ac.uk 
 
Protocol Statistician 
Terry Fenton, Sc.D. 
Frontier Science & Technology Research  
Foundation 
900 Commonwealth Avenue 
Boston, MA 02215 
Phone: 617-632-2000 x2009/617-432-3027 
Email: fenton@sdac.harvard.edu 
Protocol Statistician 
Petronella Muresan, M.S. 
Frontier Science & Technology Research  
Foundation 
900 Commonwealth Avenue 
Boston, MA 02215 
Phone: 617-632-2000 x4031 
Email: petronm@sdac.harvard.edu 
 
Protocol Data Manager 
Amanda Golner, B.S. 
Frontier Science & Technology Research 
Foundation 
4033 Maple Road 
Amherst, NY 14226-1056 
Phone: 716-834-0900 x7382 
Email: golner@fstrf.org 
Protocol Data Manager 
Bonnie Zimmer, B.S.  
Frontier Science & Technology Research 
Foundation 
4033 Maple Road 
Amherst, NY 14226-1056 
Phone: 716-834-0900 x7260 
Email: zimmer@fstrf.org 
 
 
 

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NICHD P1091 Roster (continued) 
 
Laboratory Data Manager  
Laura Hovind, M.S.  
Frontier Science & Technology Research   
Foundation 
4033 Maple Road 
Amherst, NY 14226-1056 
Phone: 716-834-0900 x7468 
Email: hovind@fstrf.org 
 
 
 

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NICHD International Site Roster 
Site #: 5071 - Instituto de Puericultura e 
Pediatria Martagao Gesteria 
Pesquisas em AIDS Materno-Infantil  
Rua Bruno Lobo No. 50 
Rio de Janeiro  
CEP 21 940 590 
Brazil 
 
Principal Investigator 
Ricardo Hugo Oliveira, M.D. 
Phone: 55-21-3148-2255 
Email: rh_oliveira@yahoo.com.br 
 
Study Coordinator 
Maria Chermont Sapia, M.D. 
Phone: 55-21-3148-2255 
Email: macher.rlk@terra.com.br  
Site #: 5072 - Hospital dos Servidores (Rio de 
Janeiro) 
Rua Sacadura Cabral, 178 
Anexo IV 4º Andar 
Saude, Rio de Janeiro 
CEP 20221-161 
Brazil 
 
Principal Investigator 
Esau Custodio Joao, M.D. 
Phone: 55-21-2233-0018 
Email: esaujoao@gmail.com  
 
Study Coordinator 
Leon Claude Sidi, M.D. 
Phone: 55-21-2203-2013 
Email: leon@diphse.com.br 
 
Site #: 5073 - FUNDEP (Belo Horizonte) 
Escola de Medicina  
Av. Alfredo Balena 90-1º Andar  
Belo Horizonte Minas Gerais 
CEP 30130-100 
Brazil 
 
Principal Investigator 
Jorge Pinto, M.D. 
Phone: 55-31-3248-9822 
Email: jpinto@medicina.ufmg.br 
 
Study Coordinator 
Flavia Faleiro, M.D. 
Phone: 55-31-3248-9822 
Email: flaviafaleiro@medicina.ufmg.br 
Site #: 5074 - University of Sao Paulo Brazil 
Ribeirão Preto Medical School  
University of Sao Paulo 
Av. Bandeirantes 3900 
Ribeirão Preto 
Sao Paulo 
Brazil 
 
Principal Investigator 
Marisa Mussi, M.D. 
Phone: 55-16-3602-2807 
Email: mmmpinha@fmrp.usp.br 
 
Study Coordinator 
Adriana A. Tiraboschi Barbaro, M.D. 
Phone: 55-16-3602-2925 
Email: a.tiraboschi@uol.com.br 
 
 
 
 

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NICHD International Site Roster (continued) 
Site #: 5084 - Universidade de Caxias do Sul 
Rua Francisco Getulio Vargas 
1130 , Bloco S, Sala 315 – Petrópolis 
Caxias do Sul 
CEP 95070-560 
Brazil 
 
Principal Investigator 
Rosa Dea Sperhacke, PharmD, Ph.D.  
Phone: 55-54-3218-2737 
Email: rdsperha@ucs.br   
 
Study Coordinator 
Silva Mariani Costamilan, B.S., R.N.  
Phone: 55-54-3218-2737 
Email: smariani@ucs.br   
 
Site #: 5097 - Hospital Geral de Nova Iguaçu 
Avenida Henrique Duque Estrada Mayer 
953 Alto da Posse - Nova Iguaçu  
Rio de Janeiro  
CEP 26030-380 
Brazil  
 
Principal Investigator 
José Henrique da Silva Pilotto, M.D. 
Phone: 5521-2667-3022 
Email: pilotto@uninet.com.br 
 
Study Coordinator 
Gisely Gonçalves Falco, R.N. 
Phone: 5521-2667-6059 
Email: gisely.falco@gmail.com  
 
Site #: 5098 - Hospital Santa Casa Porto 
Alegre Brazil 
Rua Professor Annes Dias, 295 4º Andar 
Em frente serviço de hospedagem 
Porto Alegre  
CEP 90020-090 
Brazil 
 
Principal Investigator 
Regis Kreitchmann, M.D.  
Phone: 55-51-3214-8008 
Email: regis.kr@terra.com.br 
 
Study Coordinator 
Maria Fernanda Severini, PharmB,, M.S.  
Phone: 55-51-3214-8008 
Email: fernandaseverini@terra.com.br 
Site #: 5117 - Hospital Nossa Senhora da 
Conceicao - Servico de Infectologia 
Hospital Nossa Senhora da Conceicao/GHC 
Av. Francisco Trein, 596 
Porto Alegre  
CEP 91350-200 
Brazil 
 
Principal Investigator 
Breno Riegel Santos, M.D. 
Phone: 55-51-3341-5316  
Email: breno@ghc.com.br  
 
Study Coordinator 
Rita Lira, M.D. 
Phone: 55-51-33572603 
Email: lrita@ghc.com.br 
 
 

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List of Commonly Used Abbreviations 
AE 
Adverse Event 
ANC 
Absolute Neutrophil Count 
ARV 
Antiretroviral 
BRI 
Biomedical Research Institute 
CAPiTA 
Community-Acquired Pneumonia Immunization Trial in Adults 
CBC 
Complete Blood Count 
CD4 
Cluster of Differentiation 4 
CD8 
Cluster of Differentiation 8 
CDC 
Centers for Disease Control and Prevention 
CIN 
Cervical Intraepithelial Neoplasia 
CMC 
Clinical Management Committee 
CRF 
Case Report Form 
CSF 
Cerebrospinal Fluid 
DAIDS 
Division of AIDS 
DMC 
Data Management Center 
DNA 
Deoxyribonucleic Acid 
EAE 
Expedited Adverse Event 
EC 
Ethics Committee 
EIA 
Enzyme Immunoassay 
ELISA 
Enzyme-Linked Immunosorbent Assay 
FHR 
Fetal Heart Rate 
GMCSF 
Granulocyte-Macrophage Colony-Stimulating Factor 
HAART 
Highly Active Antiretroviral Therapy 
HIV 
Human Immunodeficiency Virus 
HMPV 
Human Metapneumovirus 
HUI 
HIV-Uninfected Infants 
IFN 
Interferon 
IgG 
Immunoglobulin G 
IL2 
Interleukin-2 
IMPAACT 
International Maternal Pediatric Adolescent AIDS Clinical Trials Group 
IPD 
Invasive Pneumococcal Disease 
IRB 
Institutional Review Board 

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List of Commonly Used Abbreviations (continued) 
LAR 
Legally Authorized Representative 
LPC 
Laboratory Processing Chart 
LRTI 
Lower Respiratory Tract Infection 
MOP 
Manual of Procedures  
NaCl 
Sodium Chloride 
NICHD 
The Eunice Kennedy Shriver National Institute of Child 
 
Health and Human Development 
NICU 
Neonatal Intensive Care Unit 
NISDI 
NICHD International Site Development Initiative 
NP 
Nasopharyngeal 
NRTI 
Nucleoside Reverse Transcriptase Inhibitors 
OHRP 
Office for Human Research Protections, DHHS 
OP 
Oropharyngeal 
OPA 
Opsonophagocytic Antibodies 
PBMC 
Peripheral Blood Mononuclear Cells 
PCR 
Polymerase Chain Reaction 
PCV 
Pneumococcal Conjugate Vaccine 
PCV-10 
Pneumococcal Conjugate 10-Valent Vaccine  
PPV-23 
Pneumococcal Polysaccharide 23-Valent Vaccine 
PID 
Participant Identification Number 
PMTCT 
Prevention of Mother to Child Transmission 
PNC 
Pneumococcal 
PPV 
Pneumococcal Polysaccharides Vaccine 
RA 
Regulatory Affairs 
RE 
Regulatory Entity 
RNA 
Ribonucleic Acid 
RSC 
Regulatory Support Center 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SID 
Study Identification Number 
SMC 
Safety Monitoring Committee 
STGG 
Skim Milk-Tryptone-Glucose-Glycerin 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
 
 

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List of Commonly Used Abbreviations (continued) 
Tdap 
Tetanus, Diphtheria, Pertussis 
US 
United States 
WB 
Western Blot 
WHO 
World Health Organization 
 
 
 

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Schema 
Safety and Immunogenicity of Anti-Pneumococcal Vaccines 
in HIV-Infected Pregnant Women: NICHD P1091 
 
Design: 
Multi-center, Phase II, randomized, double-blinded, placebo-controlled. 
Sample size: 
Approximately 345 Human Immunodeficiency Virus (HIV)-infected pregnant 
women and their 345 infants (690 participants), equally distributed among three 
treatment arms to obtain ≥ 100 evaluable pairs/arm (300 total pairs, or 600 total 
participants). 
Population: 
HIV-infected pregnant women in their second or third trimester [≥ 14 weeks (14 
weeks 0 days) to < 33 weeks (32 weeks 6 days)] on highly active antiretroviral 
(ARV) therapy (HAART) and their infants. 
Regimen: 
Step 1. Pregnant women will be randomized between ≥ 14 weeks (14 weeks 0 
days) to < 33 weeks (32 weeks 6 days) of gestation to one of three blinded 
treatment arms (administered on Day 0): 
 Arm 1A: pneumococcal polysaccharide 23-valent vaccine (PPV-23); 
 Arm 1B: pneumococcal conjugate 10-valent vaccine (PCV-10); or 
 Arm 1C: placebo. 
Step 2. Women randomized to Arm 1C (placebo) who complete Step 1 will be 
screened for entry into Step 2 and will be randomized to receive PPV-23 (Arm 
2A) or PCV-10 (Arm 2B) at 24 weeks after delivery. The women who received 
active vaccine during pregnancy (Arms 1A and 1B) will stop study at 24 weeks 
after delivery.  
Step 3. Women who were initially randomized to Arm 1C and meet an exclusion 
criterion for Step 2 due to new pregnancy will be enrolled in Step 3 and receive 
open label PCV-10 at the last study visit (which coincides with Step 1 24 weeks 
post-delivery).  
All infants will receive PCV-10 per local standard of care.  
Treatment duration: Participants will receive a single vaccination at entry and one vaccination 
postpartum, if in the placebo arm. 
Study duration: 
Up to 60 weeks for women (approximately 28 weeks pre-delivery; 32 weeks post-
delivery) and up to 28 weeks for infants. 
Objectives: 
Primary: 
1. To evaluate the safety of the PCV-10 and PPV-23 vaccines in HIV-
infected pregnant women on HAART. 
2. To compare the immunogenicity of PCV-10 with PPV-23 vaccines in 
HIV-infected pregnant women on HAART. 
3. To compare the level of Pneumococcal (PNC) antibodies at 8 weeks of 
life in infants born to mothers who received PCV-10 or PPV-23 vaccines. 

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Secondary: 
1. To compare the level of transplacentally transferred vaccine-serotype 
PNC antibodies in infants born to mothers who received PCV-10 or PPV-
23 versus placebo.  
2. To compare the immunogenicity of PCV-10 and PPV-23 vaccines with 
placebo in HIV-infected pregnant women on HAART. 
3. To compare the persistence of vaccine-serotype PNC anti-capsular 
antibodies for up to 24 weeks after delivery in HIV-infected women 
vaccinated with PCV-10, PPV-23 or placebo. 
4. To compare maternal antibody responses to PPV-23 or PCV-10 
administered during pregnancy with responses to PPV-23 or PCV-10 
administered 24 weeks postpartum. 
5. To evaluate the effect of the following factors on the magnitude and 
persistence of the maternal antibody responses to PCV-10 and PPV-23: 
maternal age, ethnicity, cluster of differentiation 4 (CD4), cluster of 
differentiation 8 (CD8), plasma HIV RNA and gestational age at 
immunization. 
6. To assess potential interference of maternal antibodies with infant 
vaccine-serotype PNC anti-capsular antibody responses after the first 2 
doses of PCV-10 and determine if interference of maternal antibodies 
differs in PCV-10 from PPV-23 and from placebo recipients. 
Tertiary: 
1. To measure the incidence of pneumonia, meningitis, bacteremia and other 
manifestations of invasive pneumococcal disease (IPD) in mothers and 
infants up to 24 weeks postpartum. 
2. To measure the incidence of congenital defects in infants born to 
vaccinated and unvaccinated mothers. 
3. To assess the correlation of PNC antibodies measured by enzyme-linked 
immunosorbent assay (ELISA) and Opsonophagocytic Antibodies (OPA) 
after vaccine administration during pregnancy and of transplacentally 
transferred maternal antibodies.  
4. To assess new PNC acquisition and pharyngeal carriage in HIV-infected 
pregnant women who received PCV-10, PPV-23 or placebo (See 
Appendix IV). 
5. To assess PNC pharyngeal carriage in infants born to mothers who 
received PCV-10, PPV-23 or placebo during pregnancy. 
6. To compare the maternal B- and T-cell responses to immunization with 
PCV-10 and PPV-23 during pregnancy versus placebo. 
7. To investigate the association between B- and T-cell responses to PCV-10 
and PPV-23 with antibody persistence. 
8. To compare the maternal B- and T-cell responses to PCV-10 and PPV-23 
immunization during pregnancy and postpartum. 
9. To compare the B- and T-cell responses to childhood PCV-10 in infants 
born to mothers who received PCV-10, PPV-23 or placebo during 
pregnancy. 
 
 
 
 

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1.0 
Introduction 
 
1.1 
Background 
 
1.1.1 Burden of Pneumococcal Disease in Infants and in HIV-Infected Pregnant 
Women 
 
 
Streptococcus pneumoniae is a leading cause of bacterial pneumonia, 
meningitis and sepsis in children with and without HIV infection. In 
developing countries, 50 percent of childhood pneumonias are caused by 
Streptococcus pneumoniae and Haemophilus influenzae irrespective of 
HIV status.[1]  Pneumococcus represents 42.5 percent of bacterial isolates 
from the cerebrospinal fluid (CSF) and 19.8 percent of isolates from the 
blood of young infants in developing countries.[2]  A recent study of PNC 
disease in children 1 to 59 months of age estimated that PNC infections 
accounted for 11 percent of deaths in children of this age who were not 
infected with HIV.[3]  In Chile, 48 percent of hospitalizations due to IPD in 
children 0 to 59 months of age occurred in children in the first 5 months of 
life.[4]  Furthermore, in the Philippines, pneumococcus accounted for 6 
percent and 31 percent of invasive bacterial infections in infants younger 
than 3 months and 6 months, respectively.[5]  In Africa, up to 20 percent of 
the pediatric IPD occurs before completion of the primary immunization 
against pneumococcus.[6,7]   Widespread use of the PCV in young children 
decreases the incidence of IPD in all segments of the population, including 
un-immunized infants < 6 months of age, probably by reducing PNC 
transmission through decreasing vaccine-serotype PNC pharyngeal 
carriage in vaccinated children. In areas where PCV is used sporadically 
or not used at all, the risk of IPD in infants younger than 6 months of age 
continues. 
 
 
In HIV-infected children, pneumococcus is the most common bacterial 
infection. In HIV-uninfected infants (HUIs) born to HIV-infected mothers, 
the burden of IPD is not known. However, HUIs in developing countries 
have an increased incidence of lower respiratory tract infections (LRTIs) 
compared with children who are not exposed to HIV. The NICHD 
International Site Development Initiative (NISDI) perinatal study in Latin 
America showed that HUIs have a 21 percent incidence of LRTIs,[8] which 
is greater than that observed in a historical group of HIV-unexposed 
infants who had a 20 percent incidence of LRTIs and upper respiratory 
tract infections combined.[9]  Many of the LRTIs documented in NISDI 
were severe and required hospitalization. It must be emphasized that 76 
percent of the NISDI cohort was composed by Brazilian infants.[10] 
 
 
High prevalence of LRTIs of 15 percent was also reported in HUIs 
younger than 12 months in Africa.[11]  Viral infections, particularly 
respiratory syncytial virus, human metapneumovirus (HMPV), and other 

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respiratory viruses account for a majority of LRTIs in childhood. 
However, PNC superinfection plays an important role in the morbidity of 
viral LRTIs, as demonstrated by a 45 to 65 percent decrease in pediatric 
hospitalizations associated with influenza and HMPV in South Africa 
when PCV-9 was administered to these children.[12,13]  Furthermore, a 
recent study in France showed that compared with HIV-unexposed 
children, HUIs had increased severe pneumonia and sepsis caused by 
encapsulated bacteria including PNC.[14]  It is important to note that PCV 
has been in the childhood immunization schedule of France since 2003, 
but presumed herd immunity did not protect HUIs against PNC infection. 
A hypothesis that may explain the increased incidence of LRTIs in HUIs 
is that low maternal antibody transfer to the fetus, both antiviral and 
antibacterial, increases the susceptibility of HUIs to LRTIs during the first 
6 months of life. 
 
 
 
Pneumococcus is the leading cause of bacterial pneumonias in HIV-
infected pregnant and non-pregnant adults.[15,16,17]  Even with HAART, the 
incidence of IPD in HIV-infected individuals remains higher than that of 
same-age adults without HIV.[18,19]  IPD is the single most morbid 
vaccine-preventable condition associated with HIV infection. Bacterial 
pneumonias are more common in HIV-infected pregnant women than in 
non-pregnant HIV-infected adults;[20] are associated with premature 
deliveries and infant low birth weight;[21] and account for a significant 
proportion of maternal deaths. The mortality rate of bacterial pneumonias 
in pregnancies complicated by HIV infection is even higher than in 
uncomplicated pregnancies.[22] 
 
1.1.2 Pneumococcal Vaccines: Safety, Immunogenicity and Efficacy in HIV-
Infected Individuals 
 
 
IPD and other manifestations of PNC infection can be prevented to a great 
extent by the administration of a PNC vaccine. Two types of PNC 
vaccines are licensed in Brazil: a polysaccharide vaccine, PPV-23, 
directed against 23 serotypes and a conjugated vaccine, PCV-10, directed 
against 10 serotypes (4, 6B, 9V, 14, 18C, 19F, 23F, 1, 5, and 7F), which 
are also included in PPV-23. 
 
 
PCV is the vaccine currently recommended for immunization of children 
against pneumococcus. In HIV-infected children, PCV-7 is safe and 
immunogenic.[23]  A large efficacy trial conducted in South Africa showed 
a 65 percent efficacy of PCV-9 in HIV-infected children not receiving 
HAART and an 83 percent efficacy in uninfected children against 
serotypes contained in the vaccine. In HIV-infected and uninfected 
children there was a 50 percent and 42 percent efficacy, respectively, 
against all serotypes.[24] 
 

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Both PCV-13 and PPV-23 are currently recommended for immunization 
of adults against pneumococcus in the United States (US),[25] although 
data on the efficacy of PCV followed or preceded by PPV versus each of 
the individual vaccines are not available. Previous studies showed that 
antibody responses to PPV-23 are lower in HIV-infected participants with 
CD4 < 200 cells/µl.[26]  Nevertheless, epidemiologic studies showed that 
participants with CD4 < 200 cells/µl at vaccination may benefit from the 
protective effect of PPV-23,[27] particularly if vaccination occurs after the 
initiation of HAART. Less information on efficacy of PPV-23 is available 
for higher CD4 thresholds. However, the existing information[28] suggests 
that antibody responses are similar in patients with CD4 ≥ or < 350 
cells/µl who also have plasma viral load ≤ 10,000 HIV RNA copies/mL. 
 
 
 
Vaccination of HIV-infected individuals on no ARVs or nucleoside 
reverse transcriptase inhibitors (NRTI) monotherapy, including PPV-
23,[29] can generate transient increases in the HIV plasma viral load. Such 
increases do not have clinical consequences. Even more importantly, 
immunization of HIV-infected individuals on HAART with PCV-7 or 
PPV-23 was NOT accompanied by changes in HIV plasma viral 
load.[23,26,28,30]  This is also true for other vaccines, both live-attenuated 
and inactivated, administered to HIV-infected individuals on 
HAART.[23,31,32] 
 
 
 
The efficacy of PPV-23 for prevention of IPD and all cause pneumonias 
has been the subject of controversy. A recent Cochrane review concluded 
that it is efficacious in elderly individuals.[33]  The single prospective 
efficacy study of PPV-23 in HIV-infected adults showed that HIV-
infected Ugandans who received PPV-23 had a higher incidence of 
pneumonia compared with placebo recipients within the first 6 months 
following immunization,[34] but subsequent follow-up found a 16 percent 
reduction in all-cause mortality in PPV-23 recipients.[35]  Other 
retrospective epidemiologic studies showed efficacy of PPV-23 against 
IPD and/or pneumonia in HIV-infected adults regardless of their CD4 
counts,[27,36] with CD4 > 200 cells/µl,[37,38] ≥500 cell/µl,[39] or while 
receiving HAART.[19,37,40] 
 
 
 
Another potential problem with PPV-23 is the generation of 
hyporesponsiveness to subsequent PPV-23. Hyporesponsiveness is a 
phenomenon common to polysaccharide vaccines and is also observed 
with meningococcal polysaccharide vaccine. Hyporesponsiveness after 
PPV-23 was demonstrated in children and adults without HIV infection. 
Hence, PPV-23 is generally administered at ≥ 5-year intervals. For HIV-
infected adults who have not received any PNC vaccines, the Centers for 
Disease Control and Prevention (CDC) currently recommends 
administration of a single dose of PCV-13 followed by a first dose of 
PPV-23 ≥ 8 weeks later and a second dose of PPV-23 ≥ 5 years later. For 

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HIV-infected individuals who received PPV-23 in the past, the 
recommendation is to administer PCV-13 ≥ 1 year after the last dose of 
PPV-23. There are very few studies of immunogenicity of the proposed 
vaccination schedules and no studies of efficacy or effectiveness. There 
have not been any studies to determine the need/advantage of 
administering both PCV-13 and PPV-23, either.[41] 
 
 
 
Studies comparing the immunogenicity of PPV-23 with PCV-7 generated 
heterogeneous results. In HIV-uninfected transplant recipients and cancer 
patients, antibody responses to PCV-7 and PPV-23 did not differ 
significantly.[42,43,44,45]  In elderly HIV-uninfected adults, some studies 
showed higher antibody titers after PCV-7 and longer persistence of 
specific antibodies compared with PPV-23,[46,47] while other studies could 
not demonstrate significant differences.[48,49,50,51]  The immunogenicity of 
PPV-23 is lower in HIV-infected than in uninfected adults even in the era 
of HAART[52,53] and higher antibody titers are generally demonstrated in 
response to PCV-7 compared with PPV-23.[30,54,55]  PCV is not associated 
with hyporesponsiveness and it appears that even when administered to 
participants who received PPV-23 in the past, its immunogenicity is 
preserved. 
 
 
 
Of utmost importance are the results of a recently published study from 
Malawi demonstrating the efficacy of PCV-7 in adults with previous 
histories of IPD, including a majority of HIV-infected individuals.[56] This 
is the only prospective randomized trial that showed efficacy of any PNC 
vaccine in high-risk groups of HIV-infected adults. In addition, the 
Community-Acquired Pneumonia Immunization Trial in Adults 
(CAPiTA) study showed 40 percent efficacy of PCV in elderly adults in 
the Netherlands.[57] 
 
 
 
In summary, PCV-7 or 13 generates higher PNC antibody titers in HIV-
infected adults compared with PPV-23. In contrast to PPV-23, the use of 
PCV products is not associated with hyporesponsiveness. Furthermore, 
PCV-9 and PCV-7 are highly efficacious in protecting HIV-infected adults 
and children, respectively, against PNC. The efficacy of PPV-23 in the 
HIV-infected adults is controversial, but PPV-23 can potentially confer 
protection against a larger number of PNC serotypes, including those that 
most commonly cause disease in adults. 
 
1.1.3 Safety and Immunogenicity of Pneumococcal Vaccines Administered 
during Pregnancy 
 
 
PPV-23 is safe and immunogenic when administered during pregnancy 
uncomplicated by HIV as demonstrated by studies conducted in various 
areas of the globe, including the US, Philippines, Papua New Guinea and 
Bangladesh (Table 1-1). Taken together, these studies report on over 1,000 

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women who received PPV-23 during pregnancy. Overall, the vaccine 
increased antibody titers in the mother. Antibodies against several capsular 
PNC antigens in the vaccine were detected in cord blood and persisted in 
the infants for up to 10 months of life. Only minor local and systemic 
maternal AEs were reported. There were no obstetric complications or 
infant morbidity ascribed to the vaccine. In the study by Zaman et al., 
PPV-23 and influenza inactivated vaccine administered during pregnancy 
had similar safety profiles.[6]  In 44 HIV-infected pregnant women in 
Brazil,[40] PPV-23 had a good safety profile, but the average antibody rise 
was lower than previously reported in uninfected pregnant women. These 
women showed a decrease of the plasma HIV viral load after vaccination, 
which was most likely related to the recent introduction of ARV therapy 
for Prevention of Mother to Child Transmission (PMTCT). These data 
indicate that administration of PPV-23 does not induce HIV viral load 
increases in HIV-infected pregnant women on ARVs and are in 
accordance with our unpublished observations that administration of an 
inactivated pandemic H1N1 influenza vaccine to HIV-infected pregnant 
women who started HAART prior to or at the time of vaccination did not 
lead to any increases in the plasma HIV viral load.[58] 
 
Table 1-1. 
Reports of PPV-23 safety and/or immunogenicity in pregnancy 
 
Authors 
N 
women 
received 
PPV-23 
Study title 
Ref 
ID 
Reference 
Zaman K, Roy E, Arifeen 
SE, Rahman M, Raqib R, 
Wilson E et al. 
168* 
Effectiveness of maternal influenza 
immunization in mothers and infants 
[6] 
N Engl J Med 2008, 
359: 1555-1564 
Almeida VC, Mussi-
Pinhata MM, De Souza 
CB, Kubo CA, Martinez 
EZ, Carneiro-Sampaio MM 
et al. 
44 
Immunogenicity of 23-valent 
pneumococcal polysaccharide vaccine 
in HIV-infected pregnant women and 
kinetics of passively acquired 
antibodies in young infants 
[40] 
Vaccine 2009, 27: 
3856-3861 
Vincent-Ballereau F, 
Fortier B, Armand J, 
Lafaix C 
37 
Pneumococcal vaccination of the 
pregnant woman in Africa and passive 
immunity of the child. Immunologic 
control by the ELISA method 
[59] 
Pathol Biol (Paris) 
1985, 33: 764-767 
Riley ID, Tarr PI, Andrews 
M, Pfeiffer M, Howard R, 
Challands P et al. 
187 
Immunisation with a polyvalent 
pneumococcal vaccine. Reduction of 
adult respiratory mortality in a New 
Guinea Highlands community 
[60] 
Lancet 1977, 1: 1338-
1341 
Shahid NS, Steinhoff MC, 
Hoque SS, Begum T, 
Thompson C, Siber GR 
36 
Serum, breast milk, and infant antibody 
after maternal immunisation with 
pneumococcal vaccine 
[61] 
Lancet 1995, 346: 
1252-1257. 
 
 
 

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Table 1-1. 
Reports of PPV-23 safety and/or immunogenicity in pregnancy (continued) 
 
Authors 
N 
women 
received 
PPV-23 
Study title 
Ref 
ID 
Reference 
O’Dempsey TJ, McArdle 
T, Ceesay SJ, Banya WA, 
Demba E, Secka O et al. 
75 
Immunization with a pneumococcal 
capsular polysaccharide vaccine during 
pregnancy 
[62] 
Vaccine 1996, 14: 
963-970 
Munoz FM, Englund JA, 
Cheesman CC, Maccato 
ML, Pinell PM, Nahm MH 
et al. 
20 
Maternal immunization with 
pneumococcal polysaccharide vaccine 
in the third trimester of gestation 
[63] 
Vaccine 2001, 20: 
826-837 
Lehmann D, Pomat WS, 
Combs B, Dyke T, Alpers 
MP 
235 
Maternal immunization with 
pneumococcal polysaccharide vaccine 
in the highlands of Papua New Guinea 
[64] 
Vaccine 2002, 20: 
1837-1845 
Obaro SK, Deubzer HE, 
Newman VO, Adegbola 
RA, Greenwood BM, 
Henderson DC 
56 
Serotype-specific pneumococcal 
antibodies in breast milk of Gambian 
women immunized with a 
pneumococcal polysaccharide vaccine 
during pregnancy 
[65] 
Pediatr Infect Dis J 
2004, 23: 1023-1029 
Deubzer HE, Obaro SK, 
Newman VO, Adegbola 
RA, Greenwood BM, 
Henderson DC 
57 
Colostrum obtained from women 
vaccinated with pneumococcal vaccine 
during pregnancy inhibits epithelial 
adhesion of Streptococcus pneumoniae 
[66] 
J Infect Dis 2004, 190: 
1758-1761 
Quiambao BP, Nohynek 
HM, Kayhty H, Ollgren JP, 
Gozum LS, Gepanayao CP 
et al. 
106 
Immunogenicity and reactogenicity of 
23-valent pneumococcal 
polysaccharide vaccine among pregnant 
Filipino women and placental transfer 
of antibodies 
[67] 
Vaccine 2007, 25: 
4470-4477 
Lopes CR, Berezin EN, 
Ching TH, Canuto JS, 
Costa VO, Klering EM 
47 
Ineffectiveness for infants of 
immunization of mothers with 
pneumococcal capsular polysaccharide 
vaccine during pregnancy 
[68] 
Braz J Infect Dis 
2009, 13: 104-106 
Almeida VD, Negrini BV, 
Cervi MC, Isaac MD, 
Mussi-Pinhata MM 
45** 
Pneumococcal nasopharyngeal carriage 
among infants born to human 
immunodeficiency virus-infected 
mothers immunized with pneumococcal 
polysaccharide vaccine during gestation 
[69] 
Pediatr Infect Dis J 
2011, 30: 466-470 
Holmlund E, Nohynek H, 
Quiambao B, Ollgren J, 
Kayhty H 
106 
Mother-infant vaccination with 
pneumococcal polysaccharide vaccine: 
persistence of maternal antibodies and 
responses of infants to vaccination 
[70] 
Vaccine 2011, 29: 
4565-4575. 
* Control group received PPV-23 
**45 term HUIs born to HIV-infected mothers vaccinated with the PPV 
 

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Although PCV-10 has not been studied in pregnant women, PCV-9 was 
administered to 100 HIV-uninfected pregnant women in a recently 
published study.[71]  The publication focused on infant outcomes and 
reported a lack of AEs, along with a small, but statistically significant, 
increased incidence of acute otitis media in the first 6 months of life in 
infants born to vaccine-recipients. In a personal communication, Dr. 
Patricia Ferrieri, the senior author of the recently published study, 
confirmed the absence of serious AEs in the vaccinated pregnant women. 
 
 
Based on the evidence summarized above, that PCV preparations are more 
immunogenic than PPV-23 in HIV-infected adults, it is imperative to 
compare the safety and immunogenicity of PCV-10 with PPV-23 in HIV-
infected pregnant women, because the conjugated vaccine preparation 
may confer better protection to the mother and ensure higher PNC 
antibody transfer to the infant. It is likely that PCV-10 will be more 
immunogenic in HIV-infected pregnant women than PPV-23. This, 
however, has to be balanced against the fact that PPV-23 contains more 
antigens. 
 
1.1.4 PNC Vaccines in HIV-Infected and Uninfected Pregnant Women 
 
 
The Brazilian guidelines consider PPV-23 vaccination of HIV-infected 
adults as an optional prophylactic measure, which relies on the health care 
provider’s judgment, because it is considered controversial.[72]  No 
specific recommendations are provided for HIV-infected Brazilian 
pregnant women.[73]  However, considering the socio-epidemiological 
profile of most HIV-infected pregnant women, who are young, in a 
socioeconomic situation of vulnerability, with low schooling and 
multiparous, drug use and smoking habits,[74] it is anticipated that the risk 
of PNC infections either in the mother or in the infant is high,[75] and both 
mothers and infants would potentially benefit from maternal vaccination. 
 
 
For over 20 years, administration of PPV-23 has been recommended in the 
US for HIV-infected adults (www.CDC.gov). Although this 
recommendation does not exclude HIV-infected pregnant women, the use 
of PPV-23 during pregnancies complicated by HIV has been exceedingly 
rare. A site survey conducted by the International Maternal Pediatric 
Adolescent AIDS Clinical Trials Group (IMPAACT) PMTCT Scientific 
Committee in 2009 found that only 1 of 65 US and international sites, 
including Brazil, Argentina, Malawi, South Africa, Zimbabwe, Uganda, 
Zambia, Tanzania, India, and Thailand, administered PPV-23 to HIV-
infected pregnant women. There are several potential explanations of these 
surprising results: 
 
1. There was no definitive recommendation for PNC vaccination in 
Brazil. 

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2. Health care providers were concerned about potential adverse effects 
on mother or fetus due to lack of safety data in HIV-infected pregnant 
women. 
3. Health care providers assumed that antibody responses to PPV-23 
might be better after pregnancy and postponed vaccination. 
4. The absence of data showing the need for vaccination or proven 
potential benefits for mothers and/or infants. 
 
Barriers to administration of vaccines during pregnancy are abundant. This 
was studied with respect to seasonal influenza vaccines, which are 
recommended for all pregnant women in the US and other resource-
abundant countries.[76]  In the US, before the H1N1 2009 pandemic, only 
10 percent of pregnant women received seasonal influenza vaccines.[77]  
High levels of provider knowledge about maternal vaccination and 
positive attitudes towards influenza vaccination were identified as key 
elements favoring vaccination.[78]  In contrast, the lack of information on 
effectiveness was a common deterrent for providers,[77] whereas concerns 
about safety were invoked both by mothers and providers.[79]  After the 
2009 H1N1 influenza pandemic, which underscored the severity of 
influenza in pregnant women, the administration of influenza vaccines 
during pregnancy increased to 40-60 percent in the US. In Brazil, a 
recently published study showed 96 percent vaccination in 300 highly 
educated pregnant women.[80] 
 
 
As can be seen in Table 1-1, there are several reports showing safety and 
immunogenicity of the PPV-23 in pregnant non-HIV infected women.  In 
a single study of HIV-infected pregnant women[40] performed at a clinical 
site in Ribeirão Preto, Sao Paulo, Principal Investigator Dr. Marisa Mussi-
Pinhata demonstrated that the vaccine was safe. This clinical trial will 
enroll a larger number of HIV-infected pregnant women in each of the 
vaccine arms, thus providing extensive safety information that will be 
valuable in making the use of PNC vaccines during pregnancy acceptable 
to providers and mothers. 
 
1.1.5 Transplacental Transfer of Maternal Antibodies and Protection of Infants 
against Infections 
 
 
Maternal antibodies transferred to the infant through the placenta or breast 
milk protect infants against infections during the first few months of life. 
Administration of tetanus toxoid vaccine during pregnancy has been used 
for many decades to prevent neonatal tetanus. In recent years, maternal 
immunization against other infectious agents has been proposed with the 
objective of protecting both the mother and the infant. Zaman et al. 
showed that administration of influenza vaccines to pregnant women 

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prevented infections in mothers and infants up to 6 months after 
delivery.[6]  Subsequently, it was shown that influenza immunization of 
HIV-infected compared with uninfected pregnant women had similar 
efficacy for the mothers and for their infants.[41]  Most recently, tetanus, 
diphtheria, pertussis (Tdap) administration during pregnancy has been 
recommended and subsequently shown to be effective for protection of 
infants against whooping cough.[25] 
 
 
A similar approach was proposed for prevention of PNC infections.[61,64]  
Several studies showed that PPV-23 administered during pregnancy 
increases the serum antibody concentrations in mother and infant.[61,63,67,81]  
Riley et al. showed in Papua New Guinea that administration of PPV-23 
during pregnancy significantly decreased the incidence of LRTIs in infants 
born to vaccinated mothers compared with infants born to unvaccinated 
controls.[81]  However, these results were not universally reproduced.[68]  
IPD has a relatively high incidence in HUIs < 6 months of age[80] and 
transplacental transfer of maternal PNC antibodies at levels associated 
with protection against IPD may particularly benefit HUIs. 
 
 
The efficiency of transplacental transfer of maternal antibodies may be 
impaired in pregnancies complicated by HIV infection, such that 
vaccination of HIV-infected pregnant women may be even more relevant 
for protection of their infants when compared with HIV-uninfected 
women. Multiple mechanisms may contribute to the low transplacental 
transfer of specific antibodies in pregnancies complicated by untreated 
HIV infection, such as HIV-associated pathologic changes of the placenta, 
increased maternal levels of total Immunoglobulin G (IgG) and beta2-
microgolobulin,[82] high HIV-specific antibody concentrations[83] and co-
infections.[82,84,85]  Hence, although HIV-infected women typically have 
higher levels of naturally-acquired antibodies against PNC capsular 
antigens compared with uninfected controls,[86] their transplacental 
transfer is low.[40]  Furthermore, PNC antibodies of HIV-infected 
individuals with low CD4+ cell numbers and high plasma HIV viral loads 
have defective opsonic activity with lower serum bacterial killing and 
oxidative burst compared with antibodies of healthy participants.[87] It is 
likely that the use of HAART during pregnancy, which is currently 
recommended by the World Health Organization (WHO) and is already 
implemented in many countries for the PMTCT, will both enhance the 
quality of the PNC antibodies of HIV-infected individuals and will 
abrogate many of the conditions that hinder the transplacental transfer of 
maternal antibodies. This may translate into increased transplacental 
transfer of naturally acquired as well as vaccine-induced PNC antibodies. 
In this study, the team will examine whether maternal vaccination during 
pregnancy increases the transplacental transfer of PNC antibodies beyond 
natural infection coupled with the use of HAART and if the antibodies 

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transferred in vaccinated women have an improved functionality as 
compared with antibodies transferred after PNC infection. 
 
 
A maternal immunization program during pregnancy also has to take into 
consideration that high maternal antibody titers may interfere with infant 
responses to childhood vaccines. This is true for live attenuated vaccines, 
such as measles,[88] but was also demonstrated for inactivated vaccines, 
such as hepatitis A and  diphtheria.[89,90]  This observation did not alter the 
recommendation to administer tetanus vaccines to pregnant women when 
indicated. Conversely, there are studies suggesting that certain antigens, 
like hepatitis B, may be more immunogenic when complexed with 
antibodies.[91]  There are no studies on the interaction of maternal 
immunization against pneumococcus and responses to PNC vaccines 
during infancy. A study presented in abstract form at the 7th International 
Symposium on Pneumococci and PNC Diseases[92] showed that infants 
born to immunized mothers had slightly lower antibody responses to PCV 
administered at 6, 10 and 14 weeks of age, but still over 0.35µg/mL, 
which is considered to be protective against IPD. OPA antibody responses 
to PCV were similar in babies born to mothers with or without PPV-23 
during pregnancy. 
 
1.1.6 Surrogate Markers of Protection against Pneumococcal Disease 
 
 
Vaccine efficacy trials require large numbers of participants and intensive 
observations, characteristics that sometimes make efficacy studies 
prohibitively expensive. Surrogate markers of protection are frequently 
used to assess potential benefits conferred by vaccines. Protection against 
PNC infection was shown to correlate with robust OPA titers and with 
reduction of acquisition of vaccine-serotype PNC pharyngeal carriage. 
Serotype-specific IgG antibody concentrations of ≥ 0.35 µg/mL measured 
by ELISA have been adopted as putative measures of protection conferred 
by PCV-7 against IPD in children and will be used as infant immunologic 
endpoints in this study.  
 
 
In addition, pharyngeal carriage with Streptococcus pneumoniae precedes 
PNC disease, including IPD, and is responsible for PNC transmission in 
the community. PCV immunization of children has been associated with 
reduced risk of pharyngeal acquisition of vaccine-serotypes commonly 
associated with asymptomatic carriage in children.[93]  In contrast, PPV in 
adults has not been established to reduce pharyngeal carriage. Studies in 
mice showed that protection against pharyngeal carriage was conferred by 
PNC-specific Th17 cells[94] and evidence is accumulating that this may 
also be the case in humans.[95,96]  Since the sample size of this study will 
not be sufficient to determine the efficacy of PCV on IPD, a conservative 
proxy of likely effect on PNC disease is to explore whether PCV reduces 
acquisition of vaccine-serotypes in the women as well as in their children. 

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This may help corroborate the clinical relevance of the immunogenicity 
data in mothers and their infants. 
 
 
In areas of high PNC endemicity, 20-50 percent of adults and 50-70 
percent of infants are colonized with PNC in their upper respiratory tract. 
In infants born to HIV-infected mothers who receive cotrimoxazole 
prophylaxis, PNC pharyngeal carriage is still around 30 percent.[69]  it is 
anticipated that a moderate proportion of the mothers in this study will 
carry PNC at entry. In the maternal participants, a baseline NP and OP 
sample at the time of vaccination in Step 1 and a follow up NP and OP 
sample at delivery in order to describe the prevalence of vaccine-serotypes 
at these time points will be obtained. Using de novo acquisition of 
vaccine-serotypes in placebo recipients as the index measure, it will  be 
determined whether PPV-23 or PCV-10 decreases acquisition of vaccine-
serotypes in the mothers. 
 
 
In the absence of PCV, infants progressively develop PNC pharyngeal 
carriage as they get older and become increasingly exposed to other 
children and adults. The epidemiology of PNC acquisition and invasive 
disease in developing countries differs from industrialized countries with 
earlier pharyngeal acquisition and peak incidence of disease. Studies of 
PCV-7 have clearly demonstrated an impact on the acquisition of vaccine 
serotypes and a reduction in overall IPD in infants beginning after the 
second dose of PCV. To investigate if maternal immunization will impact 
directly on PNC pharyngeal acquisition and serotype distribution, two NP 
and OP swabs, at 8±2 weeks of life, at the time infants receive the 1st dose 
of PCV and at 16±3 weeks, when they receive the 2nd dose of vaccine will 
be collected. The hypothesis is that prevalence of carriage of vaccine 
serotypes will be reduced in children born to mothers immunized with 
PCV at the 8-week time point and that acquisition of PNC pharyngeal will 
be decreased between the 8- and 16-week visit. Identification of PNC 
carriage at 2 and 4 months of age will provide an opportunity to evaluate if 
direct protection from PNC carriage in young infants can be achieved. 
This strategy will maximize PNC detection, because over a 2-month 
interval there may be PNC serotype substitutions, additions or 
spontaneous disappearance. Acquisition of PNC by infants born to 
mothers who received placebo, PPV-23 or PCV-10 in Step 1 of the 
protocol will  be described and compared. 
 

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1.2 
Significance 
 
This study will considerably expand existing information on the safety and 
immunogenicity of PPV-23 in HIV-infected pregnant women and will determine 
for the first time the safety and immunogenicity of PCV-10 in this population. 
The study will increase the awareness of health care providers with respect to the 
safety and immunogenicity of PNC vaccines and the recommendation to 
vaccinate HIV-infected women during pregnancy. Health care providers and 
pregnant women may feel more comfortable with the administration of PNC 
vaccines as a result of the safety, immunogenicity and transplacental antibody 
transfer data that will be generated by this study. Demonstrating similar 
immunogenicity of the PNC vaccines during pregnancy and postpartum, and 
demonstrating potentially protective transplacental transfer of PNC antibodies to 
the infant, may increase the perceived benefit of PNC vaccination during 
pregnancy. It is anticipated that PCV-10 will be more immunogenic than PPV-23 
in HIV-infected pregnant women, which may change the current recommendation 
from administration of PPV-23 to administration of PCV-10 during pregnancy 
complicated by HIV. Our results may also prompt countries with a high 
prevalence of IPD, where PNC vaccines are not currently recommended for HIV-
infected adults, to consider immunization of HIV-infected pregnant women. 
 
 
 
 

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2.0 
Study Objectives 
 
2.1 
Primary Objectives 
 
2.1.1 To evaluate the safety of the PCV-10 and PPV-23 vaccines in HIV-
infected pregnant women on HAART. 
 
2.1.2 To compare the immunogenicity of PCV-10 with PPV-23 vaccines in 
HIV-infected pregnant women on HAART. 
 
2.1.3 To compare the level of PNC antibodies at 8 weeks of life in infants born 
to mothers who received PCV-10 or PPV-23 vaccines. 
 
 
2.2 
Secondary Objectives 
 
2.2.1 To compare the level of transplacentally transferred vaccine-serotype PNC 
antibodies in infants born to mothers who received PCV-10 or PPV-23 
versus placebo.  
 
2.2.2 To compare the immunogenicity of PCV-10 and PPV-23 vaccines with 
placebo in HIV-infected pregnant women on HAART. 
 
2.2.3 To compare the persistence of vaccine-serotype PNC anti-capsular 
antibodies for up to 24 weeks after delivery in HIV-infected women 
vaccinated with PCV-10, PPV-23 or placebo. 
 
2.2.4 To compare maternal antibody responses to PPV-23 or PCV-10 
administered during pregnancy with responses to PPV-23 or PCV-10 
administered 24 weeks postpartum. 
 
2.2.5 To evaluate the effect of the following factors on the magnitude and 
persistence of the maternal antibody responses to PCV-10 and PPV-23: 
maternal age, ethnicity, CD4, CD8, plasma HIV RNA and gestational age 
at immunization. 
 
2.2.6 To assess potential interference of maternal antibodies with infant 
vaccine-serotype PNC anti-capsular antibody responses after the first 2 
doses of PCV-10 and determine if interference of maternal antibodies 
differs in PCV-10 from PPV-23 and from placebo recipients. 
 
 
2.3 
Tertiary Objectives 
 
2.3.1 To measure the incidence of pneumonia, meningitis, bacteremia and other 
manifestations of IPD in mothers and infants up to 24 weeks postpartum. 

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2.3.2 To measure the incidence of congenital defects in infants born to 
vaccinated and unvaccinated mothers. 
 
2.3.3 To assess the correlation of PNC antibodies measured by ELISA and OPA 
after vaccine administration during pregnancy and of transplacentally 
transferred maternal antibodies.  
 
2.3.4 To assess new PNC acquisition and pharyngeal carriage in HIV-infected 
pregnant women who received PCV-10, PPV-23 or placebo (See 
Appendix IV). 
 
2.3.5 To assess PNC pharyngeal carriage in infants born to mothers who 
received PCV-10, PPV-23 or placebo during pregnancy. 
 
2.3.6 To compare the maternal B- and T-cell responses to immunization with 
PCV-10 and PPV-23 during pregnancy versus placebo. 
 
2.3.7 To investigate the association between B- and T-cell responses to PCV-10 
and PPV-23 with antibody persistence. 
 
2.3.8 To compare the maternal B- and T-cell responses to PCV-10 and PPV-23 
immunization during pregnancy and postpartum. 
 
2.3.9 To compare the B- and T-cell responses to childhood PCV-10 in infants 
born to mothers who received PCV-10, PPV-23 or placebo during 
pregnancy. 

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3.0 
Study Design 
 
This is a multi-center, Phase II, randomized, double-blinded, placebo-controlled study of 
345 HIV-infected pregnant women on HAART who are in the second or third trimester of 
pregnancy [≥ 14weeks (14 weeks 0 days) to < 33 weeks (32 weeks 6 days)], and their 
infants. This study is designed to investigate the safety, reactogenicity, immunogenicity, 
transplacental antibody transfer and interference with infant responses to childhood 
vaccination of maternal vaccination with PCV-10 or PPV-23 by comparison with placebo. 
 
Step 1. At entry, mothers will be randomized to one of three arms: Arm 1A (PPV-23), 
Arm 1B (PCV-10), or Arm 1C (placebo) in a blinded fashion. They will receive one 
immunization on Day 0. They will be followed for safety, immunogenicity and vaccine-
specific anti-capsular PNC antibody persistence until 24 weeks post-delivery. The women 
who received active vaccine during pregnancy (Arms 1A and 1B) will stop study at the 24 
weeks post-delivery visit. 
 
Step 2. Women randomized to Arm 1C (placebo) who complete Step 1 will be screened 
for entry into Step 2 and will be randomized to receive PPV-23 (Arm 2A) or PCV-10 
(Arm 2B) at 24 weeks post-delivery. Enrollment into Step 2 may occur during the week 
24 visit (at the time of randomization) or within 10 days of this visit (at Day 0, Step 2). 
The antibody responses to the vaccines administered 6 months postpartum will be 
measured 28 days after vaccination, i.e., approximately 7 months postpartum. The length 
of time between vaccine administration and immunogenicity testing is similar during 
pregnancy and postpartum. 
 
Step 3. Women who were initially randomized to Arm 1C and meet an exclusion criterion 
for Step 2 due to ongoing new pregnancy will be enrolled in Step 3 and receive open label 
PCV-10 at the last study visit (which coincides with Step 1 24 weeks post-delivery). No 
data will be collected on these women and they will not be followed on study after the 
vaccine administration.  
 
All infants will receive PCV-10 vaccinations per local standard of care.  
 
 
 

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4.0 
Selection and Enrollment of Participants 
 
4.1 
Step 1 – Inclusion Criteria for Pregnant Women 
 
4.1.1 Pregnant women ≥ 18 years old who provide written informed consent 
prior to study initiation. 
 
4.1.2 Pregnant women < 18 years old with parent or legal guardian able and 
willing to provide signed informed consent, or who have the capacity to 
consent for themselves, as defined by the local Institutional Review Board 
(IRB), and who provide written informed consent prior to study initiation. 
 
4.1.3 Gestational age [≥ 14 weeks (14 weeks 0 days) to < 33 weeks (32 weeks 6 
days)] documented by the approximate date of the last menstrual period 
and corroborated by ultrasound if obtained as per local standard of care. 
Results of the ultrasound will be recorded on the Abdominal Ultrasound  
Form. 
 
4.1.4 Documentation of HIV-1 infection defined as positive results from two 
samples collected at different time points as per standard of care. Results 
and source documentation may be obtained from the medical records. 
 
The following diagnostic methods are acceptable, but testing must be done 
on two different specimens: 
 Two rapid antibody tests from different manufacturers or based on 
different principles and epitopes. 
 One rapid antibody test AND one [enzyme immunoassay (EIA) from a 
different manufacturer or using different epitopes than the rapid 
antibody test OR Western blot (WB) OR immunofluorescence OR 
chemiluminescence] . 
 One EIA AND one [WB OR immunofluorescence OR 
chemiluminescence]. 
 One HIV combination antigen/antibody assay  AND one [enzyme 
immunoassay (EIA) from a different manufacturer than the combo test 
OR Western blot (WB) OR immunofluorescence OR 
chemiluminescence OR rapid antibody test from a different 
manufacturer than the combo test]. 
 One HIV DNA polymerase chain reaction (PCR). 
 One HIV RNA PCR. 
 
 

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 One HIV culture (prior to August 2009). 
 One total HIV nucleic acid. 
4.1.5 Receipt of HAART (a regimen of at least three ARV drugs) for ≥ 4 weeks 
prior to enrollment.  
 
4.1.6 Documented platelet count of  > 50,000/mm3 and an absolute neutrophil 
count (ANC) of > 500/ mm3 ≤ 28 days prior to study entry. 
 
4.1.7 Women who are willing and able to comply with the study visits. 
 
 
4.2 
Step 1 – Exclusion Criteria for Pregnant Women 
 
4.2.1 Receipt of any PCV or PPV-23 at any time prior to enrollment, 
documented by medical history or record. 
4.2.2 Receipt of any live licensed vaccine ≤ 4 weeks or inactivated licensed 
vaccine ≤ 2 weeks prior to study entry. 
4.2.3  Receipt of a non-licensed agent (vaccine, drug, biologic, device, blood 
product, or medication) ≤ 4 weeks prior to enrollment in this study, or 
expectations to receive another non-licensed agent before delivery unless 
approval from the protocol team is obtained. 
4.2.4 Any significant (in the opinion of the site investigator) acute illness and/or 
oral temperature greater than or equal to 100.4F ≤ 24 hours prior to study 
entry. 
4.2.5 Women who plan to terminate their pregnancy. 
4.2.6 Women who have a prior history of lupus or other autoimmune disorders. 
4.2.7 Use of anti-cancer systemic chemotherapy or radiation therapy ≤ 48 weeks 
of study enrollment, or evidence of immunosuppression as a result of an 
underlying illness (other than HIV-1 infection) or treatment. 
4.2.8 Ongoing neoplastic disease (excluding non-melanoma skin cancer, and 
human papilloma virus-related cervical dysplasia, cervical intraepithelial 
neoplasia (CIN) grades 1, 2 or 3). 
4.2.9 Long term use of glucocorticoids, including oral or parenteral prednisone 
≥ 20 mg/day or equivalent for more than 2 consecutive weeks (or 2 weeks 
total) within 12 weeks of study entry. 

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4.2.10 Women who received last dose of corticosteroids for preterm labor ≤ 1 
week prior to study entry. Note: A woman can be enrolled if more than 1 
week has elapsed from the last dose of corticosteroids, i.e., enrollment 
may be delayed to satisfy this criterion. 
4.2.11 Receipt of immunoglobulin or other blood products (with exception of 
Rho D immune globulin) ≤ 12 weeks prior to enrollment in this study or is 
scheduled to receive immunoglobulin or other blood products (with the 
exception of Rho D immune globulin) during pregnancy or for the first 24 
weeks after delivery. 
4.2.12 Receipt of Interleukin-2 (IL2), interferon (IFN), granulocyte-macrophage 
colony-stimulating factor (GMCSF) or other immune mediators ≤ 12 
weeks before enrollment. 
4.2.13 History of a severe adverse reaction to inactivated polysaccharide or 
conjugated vaccines. 
4.2.14 Any condition that would, in the opinion of the site investigator, place the 
participant at an unacceptable risk of injury or render the participant 
unable to meet the requirements of the protocol. 
4.2.15 Pregnancy complications (in the current pregnancy) such as pre-term 
labor, and pre-eclampsia or any other pregnancy related complication, 
which in the opinion of the investigator might jeopardize the results of the 
study. 
4.2.16 Chronic hepatitis B infection that may require administration of Hepatitis 
B Hyperimmune Globulin to neonates. 
 
 
4.3 
Step 2 – Inclusion Criteria for Women 
 
4.3.1 24 weeks ± 4 weeks postpartum. 
 
4.3.2 Completion of Step 1. 
 
4.3.3 Receipt of placebo on Step 1. 
 
 
4.4 
Step 2 – Exclusion Criteria for Women 
 
4.4.1 Pregnancy. 
4.4.2 Receipt of any live licensed vaccine ≤ 4 weeks or inactivated licensed 
vaccine ≤ 2 weeks prior to Step 2 entry*. 

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4.4.3 Receipt of a non-licensed agent (vaccine, drug, biologic, device, blood 
product, or medication) ≤ 4 weeks prior to vaccination, or expects to 
receive another non-licensed agent within 28 days after vaccination*. 
4.4.4 Any significant (in the opinion of the site investigator) acute illness and/or 
oral temperature greater than or equal to 100.4F within 24 hours of entry 
except when, in the opinion of the physician, withholding the agent entails 
even greater risk*. 
4.4.5 Use of anti-cancer systemic chemotherapy or radiation therapy or has 
developed immunosuppression as a result of an underlying illness (other 
than HIV-1 infection) or treatment. 
4.4.6 Use of glucocorticoids, including oral or parenteral prednisone ≥ 20 
mg/day or equivalent for more than 2 consecutive weeks (or 2 weeks total) 
within 2 weeks of entry in Step 2*.  
4.4.7 Receipt of immunoglobulin or other blood products (with exception of 
Rho D immune globulin) within 12 weeks prior to entry in Step 2 or is 
scheduled to receive immunoglobulin or other blood products (with the 
exception of Rho D immune globulin) during the 28 days following 
vaccination*. 
4.4.8 Receipt of IL2, IFN, GMCSF or other immune mediators ≤ 12 weeks 
before entry in Step 2*. 
*NOTE: Entry in Step 2 may be deferred for up to 4 weeks to allow for resolution of a condition/ 
event in exclusion criteria 4.4.2, 4.4.3 or 4.4.4, 4.4.6, 4.4.7, and 4.4.8. The clinical site coordinator 
needs to obtain approval from the protocol team to defer participant entry in Step 2 beyond the 
window allowed by the Schedule of Evaluations.  
 
 
4.5 
Step 3 – Inclusion Criteria for Women 
 
4.3.1  24 weeks ± 4 weeks postpartum. 
 
4.3.2 Completion of Step 1. 
 
4.3.3 Receipt of placebo on Step 1. 
 
4.3.4 Met Step 2 exclusion criterion 4.4.1. 
 
 
4.6 
Step 3 – Exclusion Criteria for Women 
 
None. 
 

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4.7 
Concomitant Medication Guidelines 
 
Administration of any medication, therapies and vaccines will be documented in 
the study case report forms (CRFs). Concomitant medications will include all 
medications and vaccines 12 weeks prior to enrollment through end of study or 
early termination, whichever occurs first. 
 
4.7.1 Vaccines 
 
 
Receipt of any maternal and infant vaccines besides the study product and 
that do not meet exclusion criteria will be collected throughout the study 
from enrollment to the off study visit. The administration of inactivated 
licensed vaccines to the mother should be at least 2 weeks prior to the 
administration of the study vaccine or delayed until 2 weeks after the 
study vaccine has been administered.  
 
 
The administration of live vaccines is contra-indicated during pregnancy. 
After delivery, live vaccines are permitted but should not be administered 
≤ 4 weeks prior to study vaccine administration in Step 2 or should be 
delayed until 2 weeks after the study vaccine has been administered. 
 
 
Administration of any anti-PNC vaccines to the mothers, other than the 
study product, is not permitted while on study. 
 
4.7.2 Disallowed/Precautionary Medications 
 
 
The following medications should be avoided, if possible, and alternative 
treatments sought. Medications that might interfere with the evaluation of 
the investigational product should not be used unless absolutely necessary. 
Medications in this category include, but are not limited to:  
 
 Glucocorticoids, i.e., oral, parenteral and high-dose inhaled steroids. 
 Immunosuppressive or cytotoxic drugs. 
 Intravenous immunoglobulin or other IgG preparations other than 
Rhogam. 
 Anti-PNC vaccines other than the study products. 
 
4.8 
Enrollment Procedures 
 
Prior to implementation of this protocol, and any subsequent full version 
amendments, each site must have the protocol document and the protocol consent 
form(s) approved, as appropriate, by their local IRB/Ethics Committee (EC) and 
any other applicable regulatory entity (RE). 

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4.8.1 Enrollment to Step 1 
 
 
Participants meeting the study eligibility criteria will be enrolled through 
the DMC registration screens. Written informed consent for study 
participation must be obtained before any study-related procedures are 
performed. Participants registered to Step 1 will be randomly assigned to 
receive PPV-23, PCV-10 or placebo in a blinded fashion. 
 
4.8.2 Enrollment to Step 2 
 
 
Participants from Arm 1C will be enrolled into Step 2 at the week 24 
postpartum visit (or within 10 days after the week 24 visit). At this time, 
the enrollment system will randomize mothers to receive the PPV-23 or 
PCV-10 vaccine, with additional study visits to follow. Participants from 
Arms 1A and 1B will be taken off study.     
 
4.8.3 Enrollment to Step 3 
 
 
Participants from Arm 1C who were not enrolled into Step 2 at the week 
24 postpartum visit (or within 10 days after the week 24 visit) will be 
enrolled in Step 3. At this time, they will receive open label PCV-10 
vaccine, after which they will be taken off study, with no additional study 
visits to follow.  
 
 
4.9 
Co-enrollment Procedures 
 
Co-enrollment in other studies is allowed, except for protocols that would violate 
the exclusion criteria. The protocol team has to be consulted before co-
enrollments. 
 
 
4.10 
PPV-23 and PCV-10 Availability at Participating Sites 
 
Both PPV-23 and PCV-10 are licensed and available in Brazil. These vaccines 
will be provided to women through the study for protocol-defined vaccine doses. 
Infants will receive PCV-10 through local standard clinical care. 
  
 

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5.0 
Study Treatment 
 
In Step 1, women will be randomized initially to one of three blinded treatment arms: Arm 
1A (PPV-23), Arm 1B (PCV-10) or Arm 1C (placebo). 
 
In Step 2, women who were randomized to Arm 1C (placebo arm) will be randomized 
again at 24 weeks postpartum to one of two blinded treatment arms: PPV-23 (Arm 2A) or 
PCV-10 (Arm 2B). Women who were initially randomized to Arm 1C and meet an 
exclusion criterion for Step 2 due to new pregnancy will be enrolled in Step 3 and will 
receive open label PCV-10 at the last study visit (Step 1 24 weeks post-delivery). 
 
All infants will receive PCV-10 per local standard of care.  
 
5.1 
Drug Regimens, Administration and Duration 
 
Step 1 
 
 Entry. At entry into Step 1, women will be randomized to one of the 
following three blinded treatment arms: 
– 
Arm 1A (PPV-23). Women in Arm 1A will be administered a 0.5 mL 
dose of PPV-23 intramuscularly once. 
– 
Arm 1B (PCV-10). Women in Arm 1B will be administered a 0.5 mL 
dose of PCV-10 intramuscularly once. 
– 
Arm 1C (placebo). Women in Arm 1C will be administered a 0.5 mL 
dose of 0.9 percent Sodium Chloride (NaCl) intramuscularly once. 
Step 2 
 
 24 weeks Postpartum. Upon entry into Step 2 at 24 weeks postpartum, 
women who were randomized to Arm 1C (placebo arm) will be randomized 
again to one of two blinded treatment arms:  
– 
Arm 2A (PPV-23). Women in Arm 2A will be administered a 0.5 mL 
dose of PPV-23 intramuscularly once. 
– 
Arm 2B (PCV-10). Women in Arm 2B will be administered a 0.5 mL 
dose of PCV-10 intramuscularly once. 
– 
A new prescription must be written with a new Study Identification 
number (SID) when registering participants to Step 2. 
 
 

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Step 3 
 
 24 weeks Postpartum. The women who were randomized to Arm 1C 
(placebo arm)  and who failed the entry into Step 2 at 24 weeks postpartum 
due to ongoing new pregnancy, will be administered a 0.5 mL dose of PCV-
10 intramuscularly once.  
A new prescription must be written with a new Study Identification number (SID) 
when registering participants to Step 3. 
 
 
5.2 
Study Product Formulation  
 
PPV-23 (Pneumovax 23®) is a clear liquid injectable vaccine supplied as 0.5 mL 
dose per single dose vial. PPV-23 is manufactured by Merck & Co., Inc. Store 
PPV-23 single dose vial refrigerated at 2°C to 8°C. Do not freeze. 
 
PCV-10 is a suspension injectable vaccine supplied as 0.5 mL per single dose vial 
(preferred) and 1 mL per multi dose vial. PCV-10 is manufactured by Glaxo-
SmithKline, Inc. Store PCV-10 vials refrigerated at 2°C to 8°C. Do not freeze. 
 
NaCl for injection 0.9 percent non-bacteriostatic, single dose vials must be 
purchased by the site locally. For the purpose of this study and to maintain 
blinding of the study product, store NaCl for injection 0.9 percent non-
bacteriostatic, single dose vial refrigerated at 2°C to 8°C if it is in accordance 
with the manufacturer’s storage recommendation. 
 
 
5.3 
Pharmacy Procedures   
 
 Study Product Acquisition  
– 
NaCl will be purchased locally. PPV-23 and PCV-10 will be provided 
through the coordinating pharmacy at site 5074, University of Sao Paulo 
Brazil Ribeirão Preto Medical School. Please refer to the most current 
version of the MOP and the Drug Distribution Plan, available on the 
NICHD website for further details on study product acquisition. 
 Study Product Accountability, Preparation, Distribution, and Destruction  
– 
The Pharmacy general procedures to be followed by the research site 
pharmacist are provided in the most current version of the Pharmacy 
Guidelines and Instructions for Division of AIDS (DAIDS) Clinical 
Trials Networks, available on the NICHD website. The ordering, 
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P1091 protocol is detailed in the MOP and in the Drug Distribution Plan 
available on the NICHD website.   
– 
Each research site pharmacist is required to maintain complete records 
of all study products received from the study coordination center or 
locally procured and subsequently dispensed including the 0.9 percent 
NaCl.  Disposal of and/or destruction of used/empty vials handled by 
the study pharmacist during the dose preparation, used study product 
syringes, vials and needles, or other materials used in preparation must 
be in accordance with site/institutional/local guidelines.  
Disposal/destruction of unused (returned, expired, remaining) study 
products should be documented in the Returns Log, available on the 
NICHD website, and kept in quarantine for monitoring review.  
 Please refer to the most current version of the MOP available on the NICHD 
website for further details on the accountability, preparation, distribution, and 
destruction of study products. 

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6.0 
Participant Management and Adverse Event Reporting 
 
6.1 
Definitions 
 
Adverse Event (AE): 
 
Any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have to 
have a causal relationship with this treatment. An AE can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding), for 
example, symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product. 
 
Serious Adverse Event (SAE):  
 
An SAE (experience) or reaction is any untoward medical occurrence that at any 
dose: results in death, is life-threatening, requires inpatient hospitalization or 
prolongation of existing hospitalization, results in persistent or significant 
disability/incapacity, or is a congenital anomaly/birth defect. Medical and scientific 
judgement should be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize 
the patient or may require intervention to prevent one of the other outcomes listed 
in the definition above. These should also usually be considered serious.  
 
Expedited Adverse Event (EAE) Form: 
 
A paper form used to document AEs that meet the seriousness criteria (SAEs) and 
need to be reported to NICHD in an expedited manner. Suspected Unexpected 
Serious Adverse Reaction (SUSAR):  
 
 A SUSAR is an event that is:  
– 
Serious (See SAE definition above).  
– 
Related (i.e., there is a reasonable possibility that the AE may be related 
to the study product).  
– 
Unexpected (see definition below).  
Unexpected Adverse Event: 
 
An AE, the nature or severity (intensity) of which is not consistent with the 
applicable agent information (Investigator’s Brochure, package insert, or 
summary of agent characteristics). 
 

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6.2 
Toxicity Management 
 
6.2.1 Women 
 
 
It is anticipated that vaccine-associated AEs will occur frequently, but that 
these will be minor local reactions and side effects. The site investigators 
will perform appropriate clinical management of AEs according to the 
situation. 
 
 
 Toxicities will be classified by the most current version of the DAIDS 
Table for Grading the Severity of Adult and Pediatric AEs 
(http://rsc.tech-res.com/safetyandpharmacovigilance). 
– 
A clinic visit is required within 72 hours from initiation of 
symptoms for maternal vaccine-related (in the opinion of the 
investigator) AEs Grade ≥ 3. Other vaccine-unrelated Grade ≥ 3 
events will be managed as per local standard of care. Vaccine-
related AEs Grade ≥ 3 need to be followed up until they reach 
Grade ≤ 2. The follow up will be recorded on the appropriate 
CRF. 
Examples of AEs of Grade ≥ 3 that may be related to the 
vaccines in the absence of an alternative explanation: 
1. Abnormal laboratory values, signs and symptoms or 
diagnoses. 
2. Local AEs, including pain, tenderness, redness, and swelling 
post vaccination. 
3. Systemic AEs, including feverishness, malaise, body aches 
(exclusive of the injection site), nausea, and headache post 
vaccination. 
4. Adverse pregnancy outcomes, including maternal, fetal and 
infant complications. 
– 
Study participants will be asked to keep a record of any AEs that 
occur within 28 days of vaccination (see Appendices V and VI) 
and report these events to the clinical personnel. ALL Grade ≥ 3 
maternal AEs regardless of association to vaccine should be 
recorded on the appropriate CRF. The Protocol Chairs and 
NICHD should be contacted [nichd.teamp1091@fstrf.org] if the 
investigator is unsure of the relationship of the toxicities to the 
study vaccine, or feels that abnormal values or events may be 
due to intercurrent infection or another drug. 
 

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6.2.2 Infants 
 
 
Infant death, congenital anomalies, prematurity, low birth weight, neonatal 
infections/sepsis, Neonatal Intensive Care Unit (NICU) admission, HIV 
transmission to infant, functional defects (hearing impairment, growth 
impairment, developmental delay) and Grade  ≥ 3 AEs will be recorded on 
the appropriate CRF and, if applicable, on the EAE Report Form.  
 
 Grade 1 and 2 infant AEs are not recorded.   
 Grade ≥ 3 infant AEs are recorded on the appropriate CRF. 
 In addition to being recorded on the appropriate CRF, all infant AEs 
that meet the criteria for expedited reporting are also recorded on the 
EAE Report Form. 
 
Management of the infant will be as per local standard of care. [Note: Low 
grade AEs (i.e., all the Grade 1 and 2 AEs) are not collected, because 
PCV-10 is licensed for use during childhood, and there are numerous and 
extensive studies of safety and reactogenicity of PCV-10 in HIV-infected 
and uninfected children around the world.] 
 
 
6.3 
Participant Management 
 
6.3.1 Screening and study entry may occur on the same day; however, entry 
may be delayed up to 28 days after screening, if needed. 
6.3.2 Maternal history at screening/entry should include all history of cancer 
and allergies, history of all immunizations received within the past 12 
weeks, status of current pregnancy and history of previous pregnancy 
complications, CDC classification for HIV status, and all medications 
taken within the past 12 weeks. Adherence to ARVs will be assessed at 
entry and at each subsequent visit using the adherence questionnaire. After 
entry, cancer, allergies, all pregnancy-related diagnoses, and current 
medications, as well as possible PNC illnesses (pneumonia, meningitis, 
sepsis, otitis media, or other lower respiratory infection) should be 
reported. All diagnoses of congenital anomalies should be reported for the 
infant. 
6.3.3 Physical exam at screening/entry should include vital signs (temperature, 
blood pressure, heart rate, and respiratory rate) and complete physical 
exam as per local standards. After entry, physical exam should include 
vital signs and targeted exam based on current signs and symptoms. 
6.3.4 Women will remain in the clinic for at least 30-60 minutes after 
vaccination in Step 1 or Step 2, so that clinic personnel can observe for 

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any potential adverse reactions to the vaccine. Equipment, supplies, and 
properly skilled medical personnel must be immediately available for 
emergency use in the event of an unexpected AE. 
6.3.5 Maternal temperature and fetal heart rate (FHR) will be measured within 
60 minutes prior to maternal vaccination and FHR will be documented 30-
60 minutes after vaccination in Step 1. 
6.3.6 Vaccine-related local (redness, swelling, tenderness, itching) and systemic 
(fever, malaise, myalgia, nausea, headache, rash, uterine cramps, 
contractions, changes in fetal movement, vaginal bleeding or discharge) 
AEs will be collected up to 28 days after immunization in Step 1 using the 
study-specific home record/diary card and/or participant interview. SAEs 
will be reported as described under Section 7.1. 
6.3.7 Antipyretics should not be routinely given in anticipation of AEs after 
vaccination, but should not be withheld if symptoms occur. Antipyretics 
should be recorded on the home record/diary card and reported to the site 
staff. 
6.3.8 Laboratory confirmed IPD in mothers and infants will be investigated and 
treated as per standard of care. IPD diagnoses can include, but are not 
limited to pneumonia, meningitis, sepsis, endocarditis, peritonitis, and 
arthritis, and should be confirmed by bacterial culture of blood, CSF or 
other appropriate specimen. If IPD is diagnosed, the following will apply: 
 Study visit (to occur as soon as possible after the IPD diagnosis and 
preferably within 3 weeks) for history and physical exam. 
 If possible, obtain an aliquot of the IPD diagnostic culture. Aliquots 
will be stored on site, and batch shipped to a central study laboratory 
for PNC serotyping (for details, see Laboratory Processing Chart 
(LPC)). 
6.3.9 Blood for Peripheral Blood Mononuclear Cells (PBMC) will be collected 
only from the first 150 women enrolled in Step 1 and all women who are 
vaccinated in Step 2. The DMC will monitor the collection of PBMCs and 
notify the sites to stop collecting these specimens once the target 
enrollment of 150 participants with available specimens has been reached. 
6.3.10 Infants will receive PCV-10 per standard of care. See Infant Schedule of 
Evaluations (Appendix II). Infant AEs are managed as per local standard 
of care. 
 
 

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6.4 
Criteria for Treatment Discontinuation 
 
 Women who receive treatment with disallowed medications, listed in Section 
4.4.3, at enrollment into Step 2 except for cases in which enrollment can be 
delayed to avoid exclusion. 
 
6.5 
Criteria for Study Discontinuation 
 
 The participant or legal guardian refuses further treatment and/or follow-up 
evaluations. 
 The investigator determines that further participation would be detrimental to 
the participant’s health or well-being. 
 The participant fails to comply with the study requirements so as to cause 
harm to him/herself or seriously interfere with the validity of the study results. 
 
6.6  
Study Results 
 
 The results of the ELISA antibody tests will be made available to study 
participants as soon as final results are available at the completion of the 
study. 
 
 

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7.0 
Expedited Adverse Event Reporting 
 
7.1 
Reporting Requirements 
 
To ensure compliance with the safety reporting requirements of the US 
regulations at 45 Code of Federal Regulations (CFR) part 46 and per the ICH-E6 
and E2A guidelines, site investigators must report immediately all AEs that meet 
the criteria for expedited reporting (SAEs), regardless of presumed relationship to 
the study product, to the Sponsor, NICHD, via the Westat Regulatory Affairs 
(RA). The Sponsor will carefully review the safety information to monitor the 
study product’s toxicity profile and patient safety. The site investigators will 
promptly notify the IRBs of any  unanticipated problems involving risks to 
subjects or to others following the institutional policies for reporting such 
information. 
 
 The study products for which expedited reporting are required are the 
following: 
– 
Maternal PPV-23, PCV-10 and placebo during pregnancy. 
– 
Maternal PPV-23 and PCV-10 after delivery. 
 AEs will be reported without knowledge of treatment arm. At the end of the 
study, when the treatment groups will be known to the protocol team, the SAE 
will be attributed to one of the active products or to placebo. 
The site investigator will report on an expedited basis any SAE following exposure 
to the study product that results in the following conditions, regardless of 
relatedness: 
1. Results in death; 
2. Is life-threatening; (the term “life-threatening” refers to an event in which the 
patient was at risk of death at the time of the event; it does not refer to an 
event which hypothetically might have caused death if it were more severe.) 
3. Requires inpatient hospitalization or prolongation of existing hospitalization; 
(per ICH SAE definition, hospitalization itself is not an AE, but is an outcome 
of the event.) 
4. Results in persistent or significant disability/incapacity; 
5. Is a congenital anomaly/birth defect; or 
6. Is an important medical event that may not be immediately life threatening or 
result in death or hospitalization but may jeopardize the patient or may require 
intervention to prevent one of the other outcomes listed in the definition above.  

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Examples include the following: intensive treatment in an emergency room or at 
home for allergic bronchospasm; blood dyscrasias or convulsions that do not 
result in hospitalization; development of drug dependency or drug abuse; etc.  
 
7.2 
Recording of Adverse Events requiring Expedited Reporting  
 
Each AE that requires expedited reporting should be recorded in standard medical 
terminology on the EAE Report Form. Whenever possible, the event should be 
evaluated and reported as a diagnosis rather than as individual signs or symptoms. 
For example, cough, runny nose, sneezing, sore throat, and head congestion 
should be reported as ‘upper respiratory infection’. If a definitive diagnosis is not 
possible, the individual signs and symptoms should be recorded.  
 
The EAE Report Form will be submitted by email or fax to the Westat RA within 
24 hours after the research staff becomes aware of the event. 
 
The investigator will evaluate all SAEs with regard to grading and relationship to 
study products. 
 
 
7.3 
Grading Severity of Adverse Events 
 
The most current version of the DAIDS Table for Grading the Severity of Adult 
and Pediatric AEs is used and is available on the Regulatory Support Center 
(RSC) web site (http://rsc.tech-res.com/Document/safetyandpharma
covigilance/DAIDS_AE_Grading_Table_v2_NOV2014.pdf). 
 
 
7.4 
Relationship to Study Products 
 
The site investigator is responsible for assessing whether there is a reasonable 
possibility that the study product caused or contributed to the AE. The 
relationship between the AE and the study product falls under two categories: 
 
 Related- there is a reasonable possibility that the AE may be related to the 
study product. 
 Not Related- there is no reasonable possibility that the AE may be related to 
the study product. An alternative etiology or explanation for the AE should be 
provided. If new information becomes available, the relationship assessment 
of any AE will be reviewed again and updated, as required. 
 
 
 

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7.5 
Expedited Adverse Event Reporting Category 
 
The SAE Reporting Category, as defined in Version 2.0 of the DAIDS EAE 
Manual, will be used for reporting AEs in an expedited manner to NICHD, via the 
Westat RA. 
 
 
7.6 
Adverse Event Reporting Period 
 
The reporting period for this protocol continues from study enrollment of an 
individual participant until study completion or discontinuation of the participant 
from study participation for any reason. 
 
After the protocol-defined AE reporting period, unless otherwise noted, only 
SUSARs will be reported to the Westat RA if the study staff become aware of the 
events on a passive basis (from publicly available information). 
 
 
7.7 
Follow-up Expedited Adverse Event Report 
 
Sites must follow each SAE until stable or resolved.  
 
The investigator should report promptly to the Westat RA any change in the 
initial EAE Report Form information or additional information that becomes 
available after the date of the initial EAE Report Form submission. 
 
 
 

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8.0 
Statistical Considerations 
 
8.1 
General Design Issues 
 
The primary objectives of this study are to assess the safety and immunogenicity 
of PPV-23 and PCV-10 multivalent vaccines in pregnant women and their infants. 
Comparisons will be made between participants receiving either of the two 
vaccine products and between those receiving vaccines versus those receiving 
placebo. With respect to immunogenicity, the study will be powered for the 
primary comparisons on which the smallest group differences are expected. This 
will provide more than sufficient power for other immunologic comparisons for 
which larger differences are expected. With respect to safety, few SAEs are 
expected; thus, the analyses will be descriptive and the study will not be powered 
for these analyses. However, the precision with which rates of AEs can be 
estimated, as well as the size of effects which can be detected with 80 percent 
power, given the sample size, will be presented below. The study will not be 
powered for the considerable number of potential secondary comparisons. 
 
A review of the literature showed that HIV-infected pregnant women, like other 
adults, have PNC antibodies before receiving PNC vaccines. However, these 
antibodies seem to be insufficient to protect them against IPD. Although maternal 
antibodies cross the placenta and are transferred to the infants, they rapidly wane and 
become undetectable by 2 months of age. Widely accepted correlates of protection 
against IPD in infants immunized with PCV-10 are ELISA-measured antibody titers 
≥ 0.35 µg/mL, but these parameters do not correlate with protection in adults. In 
adults, there is no threshold antibody level associated with protection against IPD. In 
the absence of a threshold antibody value that correlates with protection against IPD, 
response to vaccination is measured by a two-fold increase over baseline in ELISA-
measured antibody concentrations. For infants, ELISA-measured antibody titers ≥ 
0.35 µg/mL at 2 months as primary outcome measures will be used. The 2-month 
time point was chosen because the highest level of vulnerability of infants to IPD is 
in the first few months of life, before the second dose of infant PCV-10 vaccine 
confers sufficient specific antibodies to protect them against IPD. Furthermore, the 
literature suggests that, in the absence of vaccination, maternal antibodies would 
usually wane to unprotective levels by the age of 8 weeks. 
 
 
8.2 
Outcome Measures 
 
8.2.1 For Primary Objectives 
 
8.2.1.1 
Safety  
 Grade ≥ 3 AEs in mothers or in neonates; and 

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 Grade ≥ 3 AEs judged to be at least possibly related to the 
study treatment. 
8.2.1.2 
Maternal Immunogenicity 
 The serotypes measured by ELISA are: 1, 4, 5, 6B, 7F, 14, 
23F and 33F. For each serotype, a two-fold increase in 
ELISA-measured IgG PNC antibody concentrations from 
baseline to 28 days after immunization in Step 1 defines a 
response to the vaccine. The primary endpoint is a response 
to ≥ 5 serotypes. 
8.2.1.3 
Infant Immunogenicity 
 ELISA-measured IgG PNC antibody levels ≥ 0.35ug/mL at 8 
weeks of age is the primary endpoint for antibody persistence 
in the infant. Reaching this level of antibodies for ≥ 5 
serotypes listed in Section 8.2.1.2 defines success. 
8.2.2 For Secondary Objectives 
 
 The ratios of infant/mother PNC antibody levels to serotypes listed in 
Section 8.2.1.2, measured at birth/delivery; and 
 The maternal and infant immunogenicity that are described in the 
primary objective outcomes (but at different time points and from 
different groups).  
8.2.3 For Tertiary Objectives 
 
 Episodes of maternal illness possibly or probably caused by PNC; 
 Episodes of pneumonia, IPD, meningitis, acute otitis media and any 
other diseases caused by PNC in infants; 
 Changes in HIV viral load and in CD4/CD8 counts in pregnant women; 
 Infant congenital defects; 
 Mother to child HIV transmission; 
 OPA-measured antibodies to 4 PNC serotypes (4, 6B, 14 and 23F) in 
20 women who received PCV-10 and 20 women who received PPV-
23; 
 Density of PNC in NP and OP swabs at Day 0 and at delivery in 
women;   

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 Density of PNC in NP and OP swabs at weeks 8 and 16 in infants;  
 B- and T-cell responses at day 28 after vaccination and at week 24 
after delivery in mothers and at birth and 24 weeks of life in infants; 
and 
 B- and T-cell responses to childhood PCV-10 in infants born to 
mothers who received PCV-10, PPV-23 or placebo during pregnancy. 
 
8.3 
Randomization and Stratification 
 
At the Step 1 study entry, pregnant women will be randomized using a dynamic 
permuted block system to 3 groups at ratio 1:1:1, receiving PPV-23, PCV-10 or 
placebo, with approximately 115 pregnant women in each group. Women who 
received placebo in Step 1 will enter Step 2 at 24 weeks postpartum and will be 
randomized at Step 2 entry using a dynamic permuted block system to 2 groups at 
ratio 1:1 to receive PPV-23 (Arm 2A) or PCV-10 (Arm 2B). The women who 
received active vaccine during pregnancy (Arms 1A and 1B) will stop study at the 
week 24 visit. Women who were initially randomized to Arm 1C and meet an 
exclusion criterion for Step 2 due to ongoing new pregnancy will be enrolled in 
Step 3 and receive open label PCV-10 at the 24 weeks postpartum visit. No data 
will be collected on these women and they will not be followed on study after the 
vaccine administration. 
 
The participants will be unblinded following the NICHD P1091 unblinding plan 
at the end of Step 1 to unblind the participants in the placebo arm (Arm 1C) so 
they may be randomized into Step 2. All the women will be unblinded after the 
last woman has completed Step 2.  
 
 
8.4 
Sample Size and Accrual 
 
8.4.1 Sample Size Calculation 
 
8.4.1.1 
To Compare Maternal Vaccine Response 
 The proportion of mothers meeting the primary response 
criterion at 28 days after immunization will be compared 
between the groups receiving PPV-23 versus PCV-10. 
 Table 8-1, below, shows that samples of approximately 100 
evaluable participants per group will yield 80 percent 
statistical power to detect differences in response rate of 20 
percent between these two groups. 
 
 

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Table 8-1. 
Maternal response: sample sizes needed to provide 80 percent statistical power to 
detect differences in response rate as a function of PPV-23 versus PCV-10. 
 
Higher response rate 
Lower response rate 
 
.30 
.40 
.50 
.60 
.40 
376 
 
 
 
.50 
103 
408 
 
 
.60 
48 
107 
408 
 
.70 
29 
48 
103 
376 
.80 
18 
27 
44 
90 
 
8.4.1.2 
To Compare Infant Vaccine Response 
 
The proportion of infants meeting the primary maternal 
antibody persistence criterion at 8 weeks of age will be 
compared between the groups whose mothers have received 
PPV-23 versus PCV-10. Table 8-2 shows that samples of 
approximately 100 evaluable participants per group will yield 
80 percent statistical power to detect differences in response 
rate of 20 percent between these two groups. 
Table 8-2. 
Infant rate of protective antibody titers: sample sizes needed to provide 80 percent 
statistical power to detect differences in protective rate as a function of PPV-23 
versus PCV-10 
 
Higher rate of protective 
antibody titers 
Lower rate of protective antibody titers 
 
.30 
.40 
.50 
.60 
.40 
376 
 
 
 
.50 
103 
408 
 
 
.60 
48 
107 
408 
 
.70 
29 
48 
103 
376 
.80 
18 
27 
44 
90 
 
8.4.1.3 
Targeted Total Sample Size for Accrual 
 
To allow for a 10-15 percent rate of loss-to-followup, the study 
will enroll 345 mother/infant pairs (115 per group), with the 
aim of having at least 100 evaluable mother/infant pairs per 
study arm in Step 1. 
 
It is anticipated that all participants will be enrolled within 2 
years after version 1.0 becomes available. 
 
 
 

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8.5 
Monitoring 
 
Safety and tolerability of the study vaccine will be monitored by means of AEs 
and toxicity reports presenting laboratory and clinical data. The data to be 
reviewed by the Clinical Management Committee (CMC) will be pooled across 
treatment arms. It is required that these data be entered into the database within 48 
hours of the time at which the results of the laboratory tests or clinical 
examinations become available. The accrual and toxicity reports will be discussed 
by the CMC (comprised of the Protocol Chairs, Medical Officers, statisticians, 
data managers, and protocol specialist) on monthly conference calls.  
 
The attribution of relationship of AEs to study vaccine will be discussed on the 
CMC calls and the relationship will be determined by the CMC, taking into 
account the site and the Medical Officer’s assessment of the event. Interpretation 
of vaccine-relationship to AEs will be based on the type of event, the relationship 
of the event to the time of immunization, the known biology of the vaccine and 
the investigators’ medical judgment. Gradation of relationship will use the 
following terminology: “not related” or “related”.  
 
In addition to monthly toxicity reviews by the CMC, the study will be monitored 
by a Safety Monitoring Committee (SMC) who will meet yearly/ad hoc. SMC 
members will be independent of the study (except for the statistician) and have no 
financial or perceived conflict of interest. The committee will meet via conference 
call to review relevant data as described in Section 8.5.1. The Chair of the SMC 
or designee will be responsible for reporting the SMC’s comments to the protocol 
team. 
 
The Medical Officer may request for the SMC to review any safety data and for 
the SMC to be unblinded (with treatment arms labeled) or review the entire safety 
report by treatment arms, and request an immediate SMC review/meeting when 
necessary. 
 
8.5.1 Early Stopping Rules for Safety 
 
 
The following stopping rules will be applied in order to protect the study 
participants from unnecessary exposure to the vaccine, should the safety 
profile prove unacceptable in this population. 
 
 For all deaths and Grade 4 life-threatening events, excluding 
neutropenia, that are assessed by the site investigators as related to 
study treatment, vaccination will be paused until the SMC reviews the 
event and related data and determines that it is safe to resume 
vaccination. 

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 For all deaths and grade 4 life-threatening events, excluding 
neutropenia, that are assessed by the site investigators as not related, 
vaccination will continue. 
8.5.2 Early Safety Assessment by the Protocol Team 
 
 
After 20 mothers have been enrolled in each of the 3 arms, all infants have 
reached 1 month of age, and the CMC has reviewed all the blinded safety 
data, the study statistician will summarize the decisions made by the 
CMC. 
 
 
If 7 or more mothers or 7 or more infants have met a safety endpoint 
judged to be related to study treatment, then the study statistician will 
unblind the treatment assignments and summarize toxicities occurring in 
the participants receiving placebo and those receiving the PPV-23 or PCV-
10 vaccines. In collaboration with one or more SMC member(s), the 
statistician will inform the CMC whether ≥ 30 percent of the mothers or 
infants belonging to either of the maternal vaccine groups met safety 
endpoints that are vaccine-related. If this has occurred, the CMC will 
request an independent review of the data by the SMC. Otherwise, 
enrollment will continue. 
 
 
8.6 
Analyses 
 
 Safety 
For each group of mothers, the proportion of participants who experience 
grade ≥ 3 AEs up to 4 weeks after vaccination in Step 1 or Step 2 and grade 4 
AEs or death up to 24 weeks postpartum will be presented and bounded by 90 
percent confidence intervals. 
For each group of infants, the proportion of participants with congenital 
defects, in-utero or perinatal HIV infection, pneumonia or IPD will also be 
presented and bounded by 90 percent confidence intervals. 
The confidence intervals will provide 95 percent confidence that the true 
population proportion is no higher than the upper limit of the interval. The 
proportion of mothers or infants experiencing grade ≥ 3 AEs judged to be 
treatment-related will also be shown. 
Since relatively few events of this severity are expected both in vaccine- and 
placebo-recipients, these analyses will be descriptive. However, should an 
unexpected epidemic of respiratory, central nervous system, or other febrile 
illness occur during the study, there will be more AEs and a more formal 
analysis will be performed. In this case, the inclusion of the placebo group 
will allow us to examine whether the symptoms associated with these AEs are 

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significantly more prevalent among vaccines than among placebo recipients 
and should be attributed to the vaccination (Step 1 data only). 
Table 8-3 presents 90 percent confidence intervals around a range of potential 
rates of primary endpoints in a sample of 115 participants representing 
populations exposed to PPV-23, PCV-10 or placebo. These confidence 
intervals would apply to all of the endpoints defined in Section 8.2.1 for either 
the mothers or the infants. 
Table 8-3. 
90 percent confidence intervals around potential rates of grade ≥ 3 AEs within any 
of the treatment groups (N = 115) 
 
Point estimate 
Lower limit 
Upper limit 
.02 
.00 
.04 
.04 
.01 
.07 
.06 
.02 
.10 
.08 
.04 
.12 
.10 
.05 
.15 
.12 
.07 
.17 
.14 
.09 
.19 
.16 
.10 
.22 
.18 
.12 
.24 
 
Because few SAEs are anticipated, there may be limited statistical power for 
formal comparisons between groups on the basis of the proportions of 
participants meeting safety endpoints. However, the following table shows 
that, if the absolute rate of true AEs associated with one of the vaccine 
products were 8-10 percent higher than that of placebo, the sample size would 
provide reasonable power to detect such a difference. 
Table 8-4. 
Statistical power for pairwise comparisons between either of the vaccine groups and 
the placebo group with respect to the proportions of participants with grade ≥ 3 
AEs. (1-tailed Fisher’s exact tests of vaccine > placebo, alpha=.05) 
 
Vaccine group (N1)=115 
Placebo group (N2)=115 
 
.02 
.04 
.06 
.04 
.10 
NA 
NA 
.06 
.31 
.10 
NA 
.08 
.56 
.25 
.09 
.10 
.77 
.46 
.23 
.12 
.89 
.66 
.40 
.14 
.96 
.81 
.59 
.16 
.99 
.91 
.74 
.18 
.996 
.96 
.86 
 
 

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 Immunology 
– Maternal: 
1. Primary Analysis 
To compare the maternal response rates at 28 days after immunization, 
between the groups receiving PPV-23 versus PCV-10, the Chi-square 
test will be used. Logistic regression analysis may also be performed, 
should the need arise to control for certain covariates (Step 1 data 
only). 
2. Secondary Analyses 
Similar analyses to the primary analysis discussed above, comparing 
responses between placebo and each vaccination group at 28 days, will 
have 80 percent power to detect ≥ 20 percent difference in proportion 
of responders between each group of vaccines and the placebo 
recipients. Since placebo recipients are not expected to meet response 
criteria and response rates in HIV-infected pregnant women 
immunized with PPV-23 and PCV-10 have been reported to be at least 
20 percent, and often much greater, it is anticipated that the sample 
size will be sufficient to detect an effect of each vaccine compared 
with placebo (Step 1 data only). 
Similar analyses to the primary analysis comparing all groups with 
respect to immunologic response at other time points will be 
performed. Responses to the vaccine during pregnancy with responses 
after delivery (pregnancy placebo recipients vaccinated at 24 weeks 
after delivery) will also be compared. Differences in immunogenicity 
of either vaccine administered during pregnancy versus postpartum is 
not anticipated, and the study is not powered for such a comparison 
(both Step 1 and Step 2 data). 
In addition to the aggregate response, the level of PNC antibodies 
within each serotype measured will be compared at 28 days after 
immunization and at 24 weeks after delivery, among the treatment 
groups, using the baseline level as a covariate. Parametric methods 
will be used if the log-transformed titers are normally distributed, 
otherwise nonparametric analysis will be performed. Since most of the 
serotypes tested are in both vaccines, and 33F is present only in the 
PPV-23 vaccine, it is expected that women who received the PCV-10 
vaccine will have lower levels of 33F antibodies.  
For the analysis of transplacental transfer of maternal antibodies, the 
ratios of infant/mother anti-capsular antibodies for the serotypes listed 
in Section 8.2.1.2, measured at delivery/birth will be calculated. For 

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each serotype, the ratios across all three treatment groups using a 
Kruskal-Wallis test will be compared. For the serotypes for which this 
analysis is statistically significant, pairwise comparisons to see which 
groups differ from each other will be performed. 
3. Tertiary Analyses 
The incidence of pneumonia, meningitis, bacteremia and other 
manifestations of IPD between vaccine and placebo groups, during 
pregnancy and postpartum will be compared. The PNC serotypes 
associated with maternal IPD according to their presence in PCV-10 
and PPV-23, or in PPV-23 only will be grouped. Since relatively few 
cases are expected, the analysis will be descriptive (both Step 1 and 
Step 2 data). 
At the completion of the study, 60 women-infant pairs will be 
randomly selected from those who have complete antibody data (20 
women who received PCV-10, 20 who received PPV-23 and 20 who 
received placebo during pregnancy). OPA will be performed for 4 
PNC serotypes (4, 6B, 14 and 23F) at 24 days after maternal 
vaccination during pregnancy and at birth in infants. A correlation 
analysis of OPA and ELISA measured antibody levels will be 
performed in these 60 women and their infants. These will consist of 
Pearson correlations, if the data are normally distributed or Spearman 
correlations if normality assumptions are not met.   
Descriptive analyses of changes from entry in HIV viral load and in 
CD4/CD8 counts in pregnant women will be presented. 
Descriptive analyses of the density of PNC in NP and OP swabs will 
be presented. In addition, an exploratory comparison of the number of 
pharyngeal new vaccine serotype acquired after maternal vaccination 
in each group will be performed. 
PNC-specific and nonspecific B- and T-cell maternal and infant 
responses will be compared among treatment groups. Correlation 
analyses of PNC-specific B- and T-cell responses with antibody titers 
and PNC pharyngeal carriage, respectively, will also be performed.  
– Infant: 
1. Primary Analysis 
Chi-squared tests will be used to compare the proportion of infants 
meeting the primary criterion for the persistence of maternal antibody 
at 8 weeks of age between the groups whose mothers have received 
PPV-23 versus PCV-10. Logistic regression analysis may also be 

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performed, should the need arise to control for certain covariates (Step 
1 data only). 
2. Secondary Analyses 
Similar analyses to the primary analysis discussed above, comparing 
responses between placebo and each vaccination group at 8 weeks, 
will be performed. These analyses will indicate whether maternal 
vaccination provides additional infant protection, over and above that 
which would be present in the absence of vaccination. Power for these 
analyses will be similar to that described in Table 8-4,  such that power 
will be at least 80 percent to detect true differences of 20 percent or 
greater (Step 1 data only). 
Similar analyses will also compare all groups with respect to 
persistence of protective antibodies at other time points. Moreover, 
antibody responses to PNC 33F, which is part of PPV-23 but not of 
PCV-10, in infants born to mothers who received PCV-10 with infants 
born to mothers who received PPV-23 and those of infants whose 
mothers received placebo (both Step 1 and Step 2 data) will be 
compared. 
3. Tertiary Analyses 
The incidence of pneumonia, meningitis and other manifestations of 
IPD and of acute otitis media will be compared between vaccine and 
placebo groups. PNC serotypes associated with maternal IPD 
according to their presence in PCV-10 and PPV-23, or in PPV-23 will 
be grouped. Since relatively few cases are expected, the analysis will 
be descriptive (Step 1 only). 
The number of cases of mother-to-child HIV transmission will be 
summarized descriptively. 
 
 
 

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9.0 
Human Subjects 
 
This study will be conducted in compliance with the protocol, Good Clinical Practice 
Guidelines and 45 CFR Part 46. 
 
9.1 
Institutional Review Board and Informed Consent 
 
This protocol, the informed consent document (Appendix VII), and any 
subsequent modifications must be reviewed and approved by the IRB or EC 
responsible for oversight of the study prior to implementation. Written informed 
consent must be obtained from the participant (or parents or legal guardians of 
participants who cannot consent for themselves, such as those below the legal 
age). The participant’s assent must also be obtained if below legal age or if he or 
she is able to understand the nature, significance, and risks of the study. The 
informed consent will describe the purpose of the study, the procedures to be 
followed, and the risks and benefits of participation. A copy of the consent form 
will be given to the participant (or parent or legal guardian). 
 
Each site that receives US Department of Health and Human Services funding and 
follows the US  CFR Title 45-Public Welfare, Part 46-Protection of Human 
Subjects (also known as the Common Rule) should have on record at the site a 
plan that detects and addresses any change in guardianship occurring in pediatric 
participants and determines when a study participant  must have a consent process 
which involves a legally authorized representative (LAR) other than a family 
member with guardianship. LAR means an individual or judicial or other body 
authorized under applicable law to consent on behalf of a prospective participant 
to the participants involvement in the research. The plan will include how the site 
determines when an LAR is initially or no longer needed and how frequently the 
LAR re-signs the consent. The plan should follow all IRB/EC, local, state, 
national and/or host country guidelines. Confirmation of such a plan at a site 
should be submitted with protocol registration materials. 
 
 
9.2 
Participant Confidentiality 
 
All laboratory specimens, evaluation forms, reports, and other records will be 
identified only by a coded number to maintain participant confidentiality. All 
records will be kept in a secured area with limited access. All computer entry and 
networking programs will be done with coded numbers only. Clinical information 
will not be released without written permission of the participant, except as 
necessary for monitoring by the Office for Human Research Protections (OHRP), 
the local IRB or EC, local or national regulatory agencies, NICHD, study staff, 
study monitors, and other sponsors, as applicable. 
 
The Protocol Chairs and all employees and coworkers involved with this study 
may not disclose or use for any purpose other than performance of the study, any 

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data, record, or other unpublished confidential information disclosed to those 
individuals for the purpose of the study. Prior written agreement from NICHD 
must be obtained for the disclosure of any said confidential information to other 
parties. 
 
 
9.3 
Study Discontinuation 
 
The study may be discontinued at any time by the NICHD, OHRP, the IRB or EC, 
other governmental agencies, or local or national regulatory agencies as part of 
their duties to ensure that research participants are protected. 
 
 
 
 

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10.0 
Publication of Research Findings 
 
Publication of the results of this trial will be governed by NICHD policies. Any 
presentation, abstract, or manuscript will be made available for review prior to 
submission. 
 
 
 

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11.0 
Biohazard Containment 
 
As the transmission of HIV and other bloodborne pathogens can occur through contact 
with contaminated needles, blood, and blood products, appropriate blood and secretion 
precautions will be employed by all personnel in the drawing of blood and shipping and 
handling of all specimens for this study, as currently recommended by the CDC. 
 
All infectious specimens will be transported in compliance with Federal Regulations and 
the International Air Transport Association Dangerous Goods Regulations-Packing 
Instruction 602. Refer to individual carrier guidelines (e.g., Federal Express or Airborne) 
for specific instructions and to the Guidelines for Shipment and Receipt of Category B 
Biological Substance Shipment and Instruction for Overnight Shipments documents at 
https://www.hanc.info/labs/labresources/procedures/Pages/actgImpaactLabManual.aspx. 
 
 
 
 

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12.0 
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Appendix I 
Maternal Schedule of Evaluations 
Event 
Screening1 
Step 1 
Step 2 
(For women from  
Arm1C only) 
Un-
scheduled 
Visit13 
Invasive 
Pneumococcal 
Disease 
(IPD)14 
Early 
Discont. 
WK 0 
Day 0 
(Entry) 
WK 
1 
WK 4 
Labor 
and 
Delivery 
24 Weeks 
Post-
Delivery10 
Day 0 
(Step 2 
Entry)11 
WK 4 
after Step 2 
Entry 
Visit Windows 
 
 
+ 3 
days 
+ 7 
days 
+ 7  
days 
± 28  
days 
+ 10  
days 
+ 7  
days 
 
 
 
Clinical Evaluations 
Informed Consent 
 
 
 
 
 
 
 
 
 
 
 
History2 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam3 
 
 
 
 
 
 
 
 
 
 
 
Documentation of Ultrasound 
Result4  
 
4 
 
 
 
 
 
 
 
 
 
Documentation of HIV Status5 
 
 
 
 
 
 
 
 
 
 
 
Fetal Heart Rate (FHR)6, 7 
 
 
 
 
 
 
 
 
 
 
 
Vaccination 
 
7 
 
 
 
 
 
 
 
 
 
Reactogenicity Assessment8 
 
 
 
 
 
 
 
 
 
 
 
Laboratory Evaluations 
Hematology9 
1 mL 
 
 
1 mL 
 
 
 
 
 
 
 
Pregnancy Test12 
 
 
 
 
 
 
 
 
 
 
 
Virology 
HIV-1 RNA PCR 
 
3 mL 
 
3 mL 
 
 
3 mL 
 
 
 
 
Immunology 
Immunophenotyping (CD4/CD8)  
 
2 mL 
 
2 ml 
 
 
2 mL 
 
 
 
 
Serum for PNC Antibodies 
 
2 mL 
 
2 mL 
2 mL 
2 mL 
 
2 mL 
 
 
 
Blood for Plasma and 
Cryopreserved PBMC15 
 
20 
mL15 
 
20 
mL16 
 
 
20 mL 
20 mL 
 
 
 
Bacteriology 
PNC Culture/Specimen Storage 
for PNC Serotyping 
 
 
 
 
 
 
 
 
 
 
 
NP and OP Swabs for PNC 
Serotyping by PCR 
 
 
 
 
 
 
 
 
 
 
 
Total Blood Volumes 
1 mL 
27 mL 0 mL 28 mL 
2 mL 
2 mL 
25 mL 
22 mL 
0 mL 
0 mL 
0 mL 

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Footnotes 
1. 
Screening and study entry may occur on the same day; however, entry may be delayed up to 28 days after screening, if needed. 
2. 
A targeted medical history is required at screening and entry, as well as subsequent clinic visits, and should include information on (see Section 6.3.2): 
 
Life-long history of cancer and allergies at the screening/entry visit. 
 
Information regarding current status of the participant’s pregnancy; history of previous pregnancy complications will be recorded at the screening/entry visit. 
 
List of medications taken currently as well as within the 12 weeks prior to enrollment, and immunizations within the past 12 weeks. 
 
CDC classification for HIV status at screening/entry and 6 months post-delivery/early discontinuation.  
 
Pregnancy-related diagnoses and diagnoses of possible PNC infection (pneumonia, meningitis, sepsis, otitis media and other lower respiratory infections) during 
study participation. 
 
Adherence questionnaires. 
3. 
At screening/entry, physical exam should include vital signs (temperature, blood pressure, heart rate, and respiratory rate) and complete physical exam according to local 
standards. After entry, physical exam should include vital signs, and a targeted exam based on current signs and symptoms. 
4. 
Ultrasound is performed as per standard of care. Results are abstracted from the medical records.  
5. 
HIV diagnosis requires testing two different specimens. If the first test was performed at an outside facility, a copy of the laboratory result is required.  
6. 
FHR will be measured within 60 minutes prior to maternal vaccination and 30-60 minutes after vaccination in Step 1. For participants that are < 20 weeks gestational 
age, monitoring of fetal heart rate is optional. Site standard of care should be implemented for these participants.  
7. 
Following administration of vaccine, observe participant in clinic for 30-60 minutes. Additionally, FHR at appropriate gestational age should be recorded at 30-60 
minutes post vaccination. 
8. 
Reactogenicity assessments will include review of participant’s home record/diary card and provision of an assessment of AEs, which includes review for any of the 
following symptoms: erythema, induration, pain and tenderness at the injection site, fever, fatigue, myalgia (exclusive of the injection site), headache, nausea and rash. 
9. 
Hematology must include complete blood count (CBC) with differential and platelet count. Platelet count (> 50,000 mm3) and ANC (> 500 mm3) results obtained 
within 28 days of enrollment can be used. All the results will be recorded on the appropriate CRF. 
10. This will be the off study visit for the women who received active vaccine during pregnancy (Arms 1A and 1B). Women from Arm 1C will be screened for entry into 
Step 2. Women enrolled in Arm 1C who do not meet an eligibility criterion to enter Step 2 due to new pregnancy, will be enrolled into Step 3 and receive open label 
PCV-10 at this visit, which will also be their last study visit. There will be no follow-up afterwards for these participants and they will be immediately taken off study. 
11. ONLY women who received placebo during pregnancy (Arm 1C) will be randomized to Step 2 to receive a PPV-23 (Arm 2A) or PCV-10 (Arm 2B) vaccination. This 
visit can be completed on the same day or within 10 days of the 24 week post-delivery visit.  
12. A urine or serum pregnancy test should be completed, and be confirmed as negative, within 24 hours prior to Step 2 immunization. 
13. Unscheduled visits are required within 72 hours for vaccine-related (in the opinion of the investigator) adverse reactions Grade ≥ 3. Laboratory evaluations may be 
conducted at this visit, if needed, in the opinion of the site investigator. 
14. This visit will only occur if the participant develops laboratory-confirmed PNC disease during the study. The visit should be scheduled as soon as possible after the 
diagnosis of IPD, and preferably within 3 weeks. If possible, obtain an aliquot of the IPD diagnostic culture. Aliquot will be stored on site, and batch shipped to the 
testing laboratory at the end of the study or earlier if requested by the protocol team for PNC serotyping. See LPC for additional collection, processing, and shipping 
information. 
15. Blood for PBMC will be collected from the first 150 women enrolled in Step 1 and all women who are vaccinated in Step 2. 
16. Collect blood for PBMC only from women who had the collection done at Day 0. 
 
 
For insufficient blood draws, priorities are as follows: 
1. 
Serum for PNC antibodies. 
2. 
Immunophenotyping. 
3. 
Plasma HIV RNA. 

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Appendix II 
Infant Schedule of Evaluations 
 
Event 
WK 0 
Birth1 
WK 8  
(≤ 7 days before 
the 1st dose of 
PCV-10)5 
WK 16 
(≤ 7 days before 
the 2nd dose of 
PCV-10)5 
WK 24 
(≥28 Days after 
the 2nd dose of 
PCV-10)6 
Invasive 
Pneumococcal 
Disease (IPD)7 
Early 
Discont. 
Visit Windows 
+7 days 
± 14 days 
± 28 days 
28 days 
 
 
Clinical Evaluations 
Interval History2 
 
 
 
 
 
 
Physical Exam3 
 
 
 
 
 
 
Immunology and Microbiology 
Serum for PNC Antibodies 
2 mL 
2 mL 
2 mL 
2 mL 
 
 
Blood for Plasma and Cryopreserved PBMC 
3 mL 
 
 
5 mL 
 
 
PNC Culture/Specimen Storage for PNC Serotyping 
 
 
 
 
 
 
NP and OP Swabs for PNC Serotyping by PCR4 
 
 
 
 
 
 
Total Blood Volumes 
5 mL 
2 mL 
2 mL 
7 mL 
0 mL 
0 mL 
 
Footnotes: 
1. 
Neonates will receive their own PID at the time of maternal study enrollment. 
2. 
Interval history will include reporting of infant death, congenital anomalies, prematurity, low birth weight, neonatal infections/sepsis, NICU admission, HIV transmission 
to infant, functional defects (hearing impairment, growth impairment, and developmental delay), breastfeeding and Grade ≥ 3  AEs, as outlined in Section 6.2.2. 
Abstract from the history pneumococcal vaccination since last visit. Infant data will be abstracted from the maternal and/or infant charts as needed. HIV test results 
should be collected and recorded through the interval history.  
3. 
Physical exam will include: height, weight, head circumference and Apgar scores (at birth). 
4. 
If the infant is breastfed, the collection of the NP and OP swabs should occur at least 1 hour after the last feeding. 
5. 
PCV-10 will be administered as per standard of care. The vaccine may be administered at an outside facility. Administration of each dose of PCV-10 will be documented 
as indicated in footnote 2. WK 8 and 16 study visits have to occur ≤ 1 week before the 1st and 2nd dose of infant PCV-10, respectively, are administered. Blood draw and 
vaccination can occur on same day as long as blood draw precedes vaccination. 
6. 
If possible, please schedule the maternal and infant visits at the same time; however please ensure that at least 28 days have passed since the infant’s second PCV-10 
immunization. 
7. 
This visit will only occur if the participant develops laboratory-confirmed PNC disease during the study. The visit should be scheduled as soon as possible after the 
diagnosis of IPD, and preferably within 3 weeks. If possible, obtain an aliquot of the IPD diagnostic culture. Aliquots will be stored on site, and batch shipped to the 
testing laboratory at the end of the study or earlier if requested by the protocol team for PNC serotyping. See LPC for additional collection, processing, and shipping 
information. 
 
For insufficient blood draws, priority is as follows: 
1. 
Serum for PNC antibodies. 
 

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Appendix III 
P1091 Protocol Testing Laboratories 
 
Oropharyngeal and nasopharyngeal swabs for PNC serotyping by PCR:* 
Stephen Ira Pelton, M.D. 
Boston University School of Medicine 
Boston Medical Center  
774 Albany Street, Room 512 
Boston, MA 02118 
Phone: (617) 414-7407 
FAX: (617) 414-5806 
Email: spelton@bu.edu 
* NOTE: All other samples (serum and plasma) are to be shipped to the Central Repository (Biomedical Research Institute 
(BRI)) for redistribution to the testing laboratories. See LPC for specific collection, processing, and shipping information. 
 
Serum for PNC antibodies by ELISA and OPA: 
David Goldblatt, MB.Ch., Ph.D., F.R.C.P., F.R.C.P.C.H.   
Great Ormond Street Hospital (GOSH)   
Immunobiology 
Institute of Child Health, University College London (UCL) 
30 Guilford Street 
London WC1N 1EH 
Phone: 020-7905-2215 
Email: d.goldblatt@ucl.ac.uk  
 
Plasma and PBMC for PNC B and T cell-mediated immunity:  
Adriana Weinberg, M.D. 
University of Colorado Denver 
Mail Stop 8604 
12700 E. 19th Avenue, Room 11126 
Aurora, CO 80045 
Phone: 303-724-4480 
Email: adriana.weinberg@ucdenver.edu 
 
Serum for PNC antibodies by ELISA: 
Marisa Mussi, M.D. 
Ribeirão Preto School of Medicine University of São Paulo 
Av. Bandeirantes 3900 
Ribeirão Preto 
Sao Paulo 
CEP 14049-900  
Brazil 
Phone: +55 16 3602 2807 
Email: mmmpinha@fmrp.usp.br 
 
 

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Appendix IV 
Instructions for Nasopharyngeal (NP) and Oropharyngeal (OP) Sample Collection 
 
 
I. 
Materials 
Dacron or Rayon swabs with plastic shaft 
2.0 mL sterile cryovials (product code: 02-681-374; Fisher Scientific) 
Skim milk-tryptone-glucose-glycerin (STGG) medium 
II. 
Technique 
1. NP samples are collected by inserting the swab through the nose until encountering 
the resistance of the pharyngeal wall (see illustration below). Swabs are swirled and 
rapidly withdrawn from the nose and inserted in the STGG medium-containing tube. 
Figure 1.  Proper technique for obtaining a NP specimen 
 
 
 
2. OP samples are collected by inserting the swab through the mouth, swirling it against 
the pharynx and tonsils, but avoiding the tongue. The individual collecting the sample 
visually follows the tip of the swab during the procedure to make sure that the correct 
sites are being sampled. 
3. The swab is inserted in the STGG tube. The shaft of the swab is broken or cut leaving 
the tip in the STGG-containing cryovial. 
4. The vial is capped and transported to the lab where the cryovials are stored at ≤ -20ºC 
until shipment. 
5. Refer to the SOE and LPC for final procedures and shipping instructions. 
 
 
 

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Appendix V 
Study Participant Information Sheet 
 
After you receive the study vaccine, and during the remainder of the study, we would like you to 
look for side effects from the vaccine, and other illnesses you may have, and report them to your 
study nurse. 
 
During the first 28 days after receiving the vaccine: 
 
Please report to your study nurse any of the following: 
 
 
Fever 
 
Rash 
 
Changes in skin appearance or sensation at the site of the shot 
 
Changes in behavior 
 
Changes in appetite 
 
Any pain or other problems that appeared after the shot and bothered you 
 
Nausea 
 
Headache 
 
Any cramps in your uterus 
 
Any contractions 
 
Any vaginal bleeding 
 
Any vaginal discharge 
 
Any changes in fetal movements 
We would like for you to keep track of these on the home record/diary card. 
 
During the study: 
 
 
We would like you to report any illnesses that you have between study visits. 
 
If you become so ill that you need to stay overnight in the hospital, please contact 
your study nurse as soon as possible. 
 
If you are prescribed antibiotics for any illness, even if you do not have to stay in the 
hospital, please contact your study nurse as soon as possible.  
Contact information: 
 

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Appendix VI 
Home Record/Diary Card for P1091 
 
NOTE for the sites: This should be formatted for your site. Please add pictures, etc. 
 
Please review the patient information sheet. Please keep track of any signs and symptoms you 
have for the first 28 days after receiving the immunization. These include: 
 
 
Fever 
 
Rash 
 
Changes in skin appearance or sensation at the site of the shot 
 
Changes in behavior 
 
Changes in appetite 
 
Any pain or other problems that appeared after the shot and bothered you 
 
Nausea 
 
Headache 
 
Any cramps in your uterus 
 
Any contractions 
 
Any vaginal bleeding 
 
Any vaginal discharge 
 
Any changes in fetal movements 
Please write down when it started and stopped and how severe it was. 
 
 
1=not severe, no changes in my routine. 
 
2=mild, I took medicine to relieve it, it changed my routine a little. 
 
3=more severe, I needed to go to the clinic. 
 
4=very severe, I needed to stay in the hospital. 
 
 

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If you took medication for it, please write that down. 
 
What happened? 
When did it start? 
When did it stop? 
How bad was it? 
What medicine did 
you take? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix VII 
Sample Informed Consent 
Safety and Immunogenicity of Anti-Pneumococcal Vaccines in HIV-Infected Pregnant 
Women: NICHD P1091 
 
INTRODUCTION 
 
You are being asked to take part in this study because you have the Human Immunodeficiency 
Virus (HIV), the virus that causes Acquired Immune Deficiency Syndrome (AIDS); are 
pregnant; and are on Highly Active Antiretroviral Therapy (HAART). The Eunice Kennedy 
Shriver National Institute of Child Health and Human Development (NICHD) supports this 
study. The doctor in charge of this study at this site is: (insert name of Principal Investigator). 
We want you to know more about the study before you decide if you want to be a part of it.  
 
This consent form will help you learn about this study. You are free to ask the study staff 
questions about this study at any time. If you agree to be in this study and let your baby take part 
in this study, you will be asked to sign this consent form. You will get to keep a copy for your 
records. 
 
Before you decide if you want to be in this study, you should know that: 
 
 You decide to be part of this study. 
 Your baby will be part of this study once you deliver. 
 You can stop being in this study at any time and this will not affect your or your baby’s 
health care at the clinic (or any other benefits she/he might have).  
 
WHY IS THIS STUDY BEING DONE? 
 
You are being asked to take part in this study about vaccines that may keep you safe from a bad 
infection known as pneumococcal disease. The disease is caused by a germ (bacterium) and can 
affect your lungs (causing pneumonia) and brain (causing meningitis). The disease can be very 
bad and cause people to die. Babies and children can get this disease, too. You can help keep 
yourself safe from pneumococcal disease with the use of vaccines. 
 
This study will compare two kinds of pneumococcal vaccines with a harmless saltwater shot that 
looks the same as the vaccine but does not do anything to fight any germs (placebo). These 
vaccines have been safely used in Brazil. The names of the vaccines are PPV-23 and PCV-10. 
We are looking at whether there are more side effects by getting the vaccine when you are 
pregnant. We are also looking at whether the levels of antibodies (your blood’s ability to fight 
germs) in response to the vaccine are as high if you get the vaccine in pregnancy compared to 
several months after delivery. Getting the vaccine during pregnancy may also increase the 
antibodies passed to the baby and help protect the baby from pneumococcal infections before 
they can get the shots themselves. Researchers need to learn more about this.  
 
 
 

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This study could help doctors make better decisions about giving pneumococcal vaccines to 
HIV-infected women when they are pregnant. 
 
Doctors will take care of you and your baby to make sure that you do not get sick from the 
pneumococcal germs during this study. If you do get sick from any germs, you will be given 
medicine. 
 
LEARNING HOW THESE VACCINES MAY HELP WOMEN SUCH AS YOURSELF 
 
Researchers have learned about PPV-23 and PCV-10 in a lot of people, including pregnant 
women, people with HIV and people who do not have HIV. This is the first study that looks at 
PPV-23 and PCV-10 in pregnant women with HIV. Also, this is the first time that PCV-10 will 
be given to pregnant women with HIV, although a similar vaccine, PCV-9, has been given to 
pregnant women with HIV. The researchers want to study PCV-10 in pregnant women with HIV 
because it may work better than PPV-23. 
 
The United States Food and Drug Administration (FDA) and the United States Centers for 
Disease Control and Prevention (CDC) said that adults and pregnant women with HIV should get 
the PPV-23 vaccine. Early PPV-23 research shows that it helps these people from getting sick. 
 
The other vaccine, PCV-10, is considered safe to use in children who have and do not have HIV. 
Different groups including the FDA, CDC, the World Health Organization (WHO), and the 
Brazilian Ministry of Health agree on the vaccine’s safety. 
 
At the end of the study, the researchers will let you know the level of antibodies that you had 
before and after vaccination and if the vaccine increased your antibodies. They will also let you 
know the level of antibodies in your baby. 
 
KEEP TAKING YOUR HAART MEDICATIONS DURING THE STUDY 
 
You will need to take your medicine to fight your HIV, and you need to take all your medicine 
so your HIV does not get worse when you get the PCV-23 or PCV-10 vaccine; if your HIV virus 
gets worse, you may give your baby HIV. 
 
You will be randomly given either PPV-23, or PCV-10, or a harmless salt water shot (placebo) 
that looks the same as the vaccine but does not do anything to fight any germs. After you have 
your baby, if you received the saltwater shot during pregnancy, you will get PPV-23 or PCV-10. 
By the end of the study, all women will get PPV-23 or PCV-10, but you will not know which 
one you got until the end of the study. All babies will get PCV-10. 
 
WHAT DO I HAVE TO DO IF I AM IN THIS STUDY? 
 
If you agree to be in this study, you will be asked some questions. By being in this study, you are 
also telling us that your baby can be in this study. 

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FOR YOU: 
 
Screening Visit (while you are pregnant): 
 
After you read and sign this consent form, you will have the following done at the screening visit 
to see if you can be in the study: 
 
 
You will be asked questions about your medical history and how often you take your 
anti-HIV medications. 
 
You will be asked if the research team can look at your medical records. 
 
You will have a physical exam that will look at your height, weight, blood pressure 
and heart rate. Your doctor may decide that you need more exams. 
 
You will have 1 mL (about ¼ teaspoon) of blood taken: 
 
For regular blood tests. 
 
This visit will take about 30 minutes. 
 
Week 0 (Entry - Day 0, day of vaccine or placebo application) (while you are pregnant): 
 
Note: This visit may occur on the same day as the screening visit. 
 
Once it is known that you can be in this study, you will have an entry visit. You will be assigned 
by chance, as if by the toss of a coin, to receive either PPV-23, or PCV-10, or a harmless 
saltwater shot (placebo). You have a 1 in 3 chance of receiving the placebo. Neither you nor your 
doctor will know whether you are receiving PPV-23, PCV-10, or the placebo. 
 
At this visit: 
 
 
You will be asked questions about your medical history and how often you take your 
anti-HIV medications. 
 
You will have a physical exam (like the one you had during the screening visit).  
 
We will check your baby’s heart rate before and about 30-60 minutes after you 
receive the vaccination. 
 
You will be given one dose of the vaccine with a needle in your upper arm. 
 
You will remain in the clinic for about 30-60 minutes after receiving the vaccine to 
make sure that you are safe after getting the vaccine and to check your baby’s heart 
rate. 
 
We will quickly put a swab into your nose, and will take a second swab from across 
the back of your throat to get samples. We will test these samples to see if you have 
the pneumococcus germ. 
 
You will be given a piece of paper (called a home record/diary card) that tells you 
what could happen. You will be asked to write down anything strange that you feel 
on this home record/diary card. 
 
You will have7 mL (about 1.5 teaspoons) of blood taken: 
 
To measure how much HIV is in your blood. 
 
To measure how your body is responding to HIV. 

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 
You may be asked to have about 20 mL (about 4 teaspoons) of blood taken for 
special blood tests to see if your body can protect yourself from the 
pneumococcus germ. You may decide not to have this additional blood drawn.  
If you decide that this additional blood may be drawn, but you are not one of 
the first 150 people enrolled, no additional blood will need to be taken. If you 
decide not to have this blood drawn, this will not affect your clinical care and 
study participation.  
 
This visit will take about 2 hours. 
 
Week 1 - Study Day 7 to 10 (while you are pregnant): 
 
At this visit: 
 
 
You will be asked questions about your medical history and how often you take your 
anti-HIV medications. 
 
You will have a physical exam to see if your body has reacted to the vaccine. 
 
You will review your home record/diary card with the study staff.  
 
This visit will take about 30 minutes. 
 
Week 4 - Study Day 28 to 35 (while you are pregnant): 
 
At this visit: 
 
 
You will review your home record/diary card with the study staff.  
 
You will have 28 mL (about 5-6 teaspoons) of blood taken: 
 
For routine blood tests.  
 
To measure how much HIV is in your blood. 
 
To measure how your body is responding to HIV. 
 
For special blood tests to see if your body can protect yourself from the 
pneumococcus germ. 
 
This visit will take about 30 minutes. 
 
Labor/Delivery Visit (while you are pregnant): 
 
This study visit will be when you come to the hospital to have your baby.  
 
At this visit: 
 
 
You will be asked questions about your medical history and how often you take your 
anti-HIV medications.  
 
Like before, we will use swabs to collect samples from your nose and throat. We will 
test these samples to see if you have the pneumococcus germ. 
 
You will have 2 mL (about ½ teaspoon) of blood taken: 
 
For special blood tests to see if your body can protect yourself from the 
pneumococcus germ.  

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24-Week Post-Delivery Visit (for you): 
 
At 24 weeks (about 6 months after you have your baby), you will be asked to come back to the 
clinic.  
 
At this visit: 
 
 
You will be told if you got the vaccine or the harmless salt water shot (placebo) 
during pregnancy. 
 
You will be asked questions about your medical history and how often you take your 
anti-HIV medications. 
 
You will have 2 mL (about ½ teaspoon) of blood taken: 
 
For special blood tests to see if your body can protect yourself from the 
pneumococcus germ. 
 
This visit will take about 30 minutes. 
 
If you received a real vaccine during pregnancy, this will be your last visit.  
 
If you received the harmless salt water shot (placebo) during pregnancy, you will be offered 
enrollment into step 2 of the study. 
 
Step 2 - Entry (Day 0, day of vaccine application for women who received placebo) on the same 
day or within 10 days of the 24-Week Post-Delivery Visit:  
 
Note: This visit may happen on the same day of the 24-week post-delivery visit. 
 
At this visit: 
 
 
You will have a physical exam and you will be asked a few questions.  A pregnancy 
test will be performed. 
 
If you are NOT pregnant and are not taking any medication that may interact with 
the study vaccine: 
 
You will be assigned by chance, as if by the toss of a coin, to receive PCV-10 
or PPV-23. The vaccine will be injected into your arm. Neither you nor your 
doctor will know which vaccine you will receive. 
 
You will have 25 mL (about 5 teaspoons) of blood taken: 
 To measure how much HIV is in your blood. 
 To measure how your body is responding to the HIV virus. 
 For special blood tests to see if your body can protect yourself from the 
pneumococcus germ. 
 
If you are pregnant, and are not receiving any medication that may interact with the 
study vaccine: 
 
You will receive PCV-10 so you can be protected by the vaccine. 
 
This will be your last study visit.  

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 
You will remain in the clinic for at least 30 minutes after the shot to make sure you 
are safe from the vaccine. 
 
This visit will take about 1 hour. 
 
Step 2 - Week 4 (28 days after Day 0, day of vaccine application for women who received 
placebo): 
 
At this visit: 
 
 
You will be asked questions about your medical history and how often you take your 
anti-HIV medications.  
 
You will have 22 mL (about 4-5 teaspoons) of blood taken: 
 
For special blood tests to see if your body can protect yourself from the 
pneumococcus germ. 
 
This visit will take about 30 minutes. 
 
Unscheduled Visit: 
 
At the beginning of the study, you will be asked to write down anything strange that happens to 
your body on a home record/diary card. At any time during the study, if you feel like something 
strange is happening to your body, you will be asked to come in to the clinic within 72 hours.  
 
At this visit: 
 
 
You will be asked questions about your medical history and how often you take your 
anti-HIV medications.  
 
You will have a physical exam.  
 
You will be taken care of by your doctor/ physician (care provider). 
 
Invasive Pneumococcal Disease (IPD) Visit: 
 
If, during the study, you or your baby gets sick and has to stay in the hospital, you will be asked 
to tell your study nurse as soon as possible. If the reason for your or your baby’s hospitalization 
was a bad infection with the pneumococcus germ, you will be asked to come to the clinic as soon 
as possible. We can do this visit while you are at the hospital.  
 
At this visit: 
 
 
You will be asked questions about your or your baby’s medical history. 
 
You or your baby will have a physical exam.  
 
You or your baby will get care from your or your baby’s doctor based on your or 
your baby’s needs and local standards. 
 
 

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 
If possible, we will get a sample from the hospital that was used to tell if you have a 
bad infection with the pneumococcus germ. This sample will be used for study-
related tests. We will not repeat any tests, and it will not cause more discomfort for 
you or your baby. 
 
Early Study Discontinuation Visit: 
 
If you no longer want to be in this study, or no longer can be in this study, you will be asked to 
come to the clinic one last time. If this visit occurs after your baby was born, we will ask you to 
bring your baby to the visit.  
 
At this visit: 
 
 
You will be asked questions about your medical history and how often you take your 
anti-HIV medications.  
 
You will review your home record/diary card with the study staff.  
 
This visit will take about 1 hour. 
 
FOR YOUR BABY: If you agree to take part in this study, your baby will be in this study. 
 
Week 0 (Day 0 - in the first hours after birth, before your baby receives hospital discharge, or 
within 7 days of birth): 
 
At this visit: 
 
 
Your baby will have a physical exam including height, weight, head size, test to see 
if your baby needs any emergency care (Apgar score), and vital signs.  
 
Your baby will have 5 mL (about 1 teaspoon) of blood taken:  
 
To check if your baby’s blood is protected from the vaccines you received. 
 
This visit will take about 1 hour. 
 
Week 8 (When your baby is 2 months of age and before he/she receives the first dose of PVC-
10): 
 
This visit will happen within 7 days before your baby receives the first dose of PCV-10.  At this 
visit: 
 
 
All babies will receive PCV-10 per local standard of care.  
 
We will collect swab samples from your baby’s nose and throat. We will test these 
samples to see if your baby has the pneumococcus germ.  
 
Your baby will have 2 mL (about ½ teaspoon) of blood taken: 
 
To check if your baby’s blood is protected from the vaccines you received. 
 
This visit will take about 1 hour. 
 

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Week 16 (When your baby is 4 months of age and before he/she receives the second dose of 
PVC-10): 
 
This visit will happen within 7 days before your baby receives the second dose of PCV-10. At 
this visit: 
 
 
As done before, we will collect swab samples from your baby’s nose and throat. We 
will test these samples to find out if your baby has the pneumococcus germ.  
 
Your baby will have 2 mL (about ½ teaspoon) of blood taken: 
 
To check if your baby’s blood is protected from the vaccine they received at 2 
months.  
 
This visit will take about 1 hour. 
 
Week 24 (When your baby is 6 months of age and at least 28 days after your baby receives the 
2nd dose of PCV-10): 
 
This visit will happen 28 days or longer after your baby receives the second dose of PCV-10. At 
this visit: 
 
 
Your baby will have 7 mL (about 1 teaspoon) of blood taken: 
 
To check if your baby’s blood is protected from the vaccine they received at 4 
months.  
 
This visit will take about 1 hour. 
 
TESTING AND STORAGE OF BLOOD SAMPLES 
 
Some of your and your child’s blood samples will be shipped to specialized laboratories in Brazil 
and outside of Brazil for testing. 
 
About 20 mL (about 4 teaspoons) of blood will be taken from the first 150 women enrolled in 
Step 1 for special blood tests to see if your body can protect yourself from the pneumococcus 
germ. 
 
Also, some of your and your baby’s blood that is left over after the study will be stored in a 
special laboratory in the United States (Fisher Bioservices Laboratory) for possible future use in 
HIV-related research. Researchers will not collect any extra samples for future research. They 
will only use what they already have. These samples sent to the United States will not have your 
or your baby’s name. The samples will have a special code, the same as the code that you and 
your baby received for the study, called a Participant Identification (PID) number. The 
documents that permit researchers to link this code to your and your baby’s information will be 
kept in a safe place in the research center, away from your and your baby’s medical charts. By 
doing this, you and your baby will be protected.  
 
 
 

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The only people who will see your and your baby’s stored samples are researchers and people 
who work at the facility and keep track of the samples. None of them will have information that 
tells them it is you and your baby. Your and your baby’s samples will not be sold or used to 
make commercial products.  
 
If a researcher wants to do a new study with your and your baby’s samples, they will ask for 
permission from NICHD. They will make sure you and your baby will be kept safe and will also 
need permission from the sites’ Institutional Review Board (IRB), the Ethics Committee of 
XXXX. Also, the Brazilian National IRB Comissão Nacional de Ética em Pesquisa (CONEP) 
will review this study to make sure that the study remains safe.  An IRB is a committee that 
watches over the safety and rights of research subjects. 
 
According to the rules, your and your baby’s samples will be kept for up to 5 years. If the study 
wants to keep your samples for more time, the researchers must be asked and provide a report 
that tells about what has been done with the samples.  
 
Your and your baby’s samples will be used only when a researcher has a new study. We do not 
know when this will be, but you have the right to know what has been done with your and your 
baby’s samples and the results of testing when there is important information to share about your 
and your baby’s health and medical care. Your local IRB will decide if you need to know the 
results of testing or the new study findings. To get this information, you must tell the study staff 
of any changes in your address or phone number. 
 
There is a small risk that someone may use your or your baby’s samples or information wrongly. 
For example, someone could find out which test results are yours and use this information to 
harm you and this could cause problems for you. For this to happen, the person would have to 
get into a database that has results with your name. To prevent this from happening, researchers 
protect this by limiting access to databases, not linking names to results, and not placing results 
in medical records.  
 
There will be no direct benefit to you or your baby from future research using your or your 
baby’s stored samples and information. However, the information learned may help others. It 
may take the researchers many years to have any results. In most cases, you will not receive 
future research results from the researchers. 
 
There is no cost to you or your baby for allowing researchers to use your samples and 
information for future research. 
 
You and your baby will not receive any money to let researchers use your or your baby’s 
samples and information for future research. However, some research may lead to new things, 
such as new medicines or tests. You and your baby will not receive any money from these new 
medicines or tests.  
 
You may decide that you do not want your and your baby’s samples to be stored for future 
research studies. You and your baby can still participate in this study even if you make this 
decision.  

NICHD P1091 
VERSION 2.0 
FINAL 
May 23, 2016 
 
Page 89 of 93 
 
You may decide that you do not want to let your and your baby’s samples be used anymore. If 
you decide you do not want these to be used anymore, the samples will be destroyed. 
 
Please read the following statement carefully and then mark your initials in the 
appropriate space provided. 
 
I agree to allow my blood samples and my baby’s blood samples to be stored for use in future 
NICHD-approved, HIV-related research studies and by the Brazilian agencies of Administrative 
and Ethics regulation. 
 
__________ Yes 
 
__________ No 
 
___/___/______ Date 
 
OTHER INFORMATION 
 
When the study is over and all the information has been looked at, you will be told by your study 
staff what vaccine you got and how well this vaccine did. You will be given the results of your 
tests. The results of special laboratory tests (to test your immune response to the vaccine) might 
be provided to you or your doctor, if requested by your doctor. Some of your blood and nose and 
throat samples will be sent to the United States for testing. 
 
The information from this study may be used for other HIV research.  
 
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY? 
 
About 345 women and their babies will take part in this study. 
 
HOW LONG WILL I/MY BABY BE IN THIS STUDY? 
 
You will be in this study for up to 60 weeks (about 28 weeks before you have your baby and 32 
weeks after you have your baby), and your baby will be in this study for up to 28 weeks. 
 
WHY WOULD THE DOCTOR TAKE ME/MY BABY OFF THIS STUDY EARLY? 
 
The study doctor may need to take you and your baby off the study early without your 
permission if: 
 
 
The study is stopped by the United States NICHD, the Office for Human Research 
Protections (OHRP), the site’s IRB, CEP-XXXXXX, or the Brazilian National IRB 
CONEP.  
 
A Safety Monitoring Committee (SMC) recommends that the study be stopped early. 
An SMC is group of people that makes sure the study is safe. 
 
You and your baby are not able to come to the study visits. 
 
 
 

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Page 90 of 93 
The study doctor may also need to take you and your baby off the study product(s) without your 
permission if: 
 
 
Continuing the study vaccine may be harmful to you or your baby. 
 
You and your baby need a treatment that you and your baby may not take while on 
the study. 
 
You and your baby are not able to take the vaccines as required by the study. 
 
During the study: 
 
If your baby needs to stop taking the PCV-10 before the study is over, the study staff will talk 
about other choices for you and your baby. The study doctor may ask you to let your baby be 
part of the study and come back for some study visits and tests.  
 
WHAT ARE THE RISKS OF THE STUDY? 
 
This study may involve risks to you or your baby which are not known.  You or your baby may 
feel faint or may feel some pain while having blood taken. There may be some tenderness, 
swelling, bleeding, or bruising where the needle goes into the skin, or a small blot clot may 
develop. There is a small risk of getting an infection where the needle goes into the skin to take 
blood. 
 
Risks Related to the Vaccines (PPV-23 or PCV-10): 
 
A vaccine, like any medicine, could cause a serious reaction. But the risk of a vaccine causing 
serious harm, or death, is extremely small. If reactions do occur, it will be within a few minutes 
to a few hours after the vaccination. Please also reference the participant information sheet you 
will receive from the study staff about the vaccines.  
 
PPV-23: 
 
About half of the people who get PPV-23 have mild side effects, such as redness or pain where 
the shot is given. Less than 1% of people develop a fever, muscle aches, or more severe 
problems.  
 
People who receive a 2nd dose of PPV-23 less than 5 years after the 1st dose may have less 
protection from the 2nd dose of vaccine.  
 
PCV-10: 
 
Some adults who receive PCV-10 may develop pain in the arm, fever, or malaise. No serious 
problems have happened from this shot.  
 
 
 

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May 23, 2016 
 
Page 91 of 93 
Placebo:  
 
Women who get the vaccine during pregnancy may prevent infection caused by the 
pneumococcus germ or lessen their symptoms if they get infected, but if they get a placebo 
(harmless saltwater shot) this may not happen until later.   
 
ARE THERE RECOMMENDATIONS RELATED TO THE STUDY? 
 
The Brazilian rules say that it is HIV-infected adults’ choice to decide whether or not to get the 
PPV-23 vaccine to prevent infections caused by the pneumococcus germ.  They rely on their 
doctors to help them decide. There are no specific recommendations for HIV-infected Brazilian 
pregnant women. 
 
ARE THERE BENEFITS TO TAKING PART IN THIS STUDY? 
 
If you and your baby take part in this study, there may be a benefit to you and your baby, but no 
promise can be made. You may prevent infection caused by the pneumococcus germ or lessen 
your symptoms if you get infected.  
 
You and your baby may receive no benefit from being in this study. It not known whether these 
vaccines will increase or decrease your baby’s risk of HIV infection, even if you and your baby 
are on medications to prevent HIV. This study may help others who have HIV. 
 
WHAT OTHER CHOICES DO I/DOES MY BABY HAVE BESIDES THIS STUDY? 
 
Instead of being in this study, you may choose to receive PPV-23 outside of the study. PPV-23 is 
available from the Ministry of Health. If you choose to receive PPV-23 outside of this study, 
your doctor will give you the vaccine if it is available in his/her office or will give you a 
prescription for this vaccine and inform you how to fill it. 
 
Please talk to your doctor about these and other choices available to you and your baby. Your 
doctor will explain the risks and benefits of these choices. 
 
WHAT ABOUT CONFIDENTIALITY? 
 
The doctors and research staff will work to keep your and your baby’s information 
confidential/private. Your and your baby’s information will be replaced by a random number 
called a code. Anything written/published about this study will not use your or your baby’s 
name. 
 
Your and your baby’s information may be looked at (without disclosing your or your baby’s 
name) by groups in the United States such as the OHRP and the NICHD, the site IRB 
(HCFMRP-USP), study staff, study monitors, and drug companies working on the study, when 
agreed on by the doctors and site staff, and in compliance with the Code of Ethics of the Federal 
Counsel of Medicine and Brazilian laws that protect study participants. 
 

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FINAL 
May 23, 2016 
 
Page 92 of 93 
A description of this clinical trial will be available on www.ClinicalTrials.gov, as required by 
U.S. law. This Web site will not include information that can identify you. At most, the Web site 
will include a summary of the results. You can search this Web site at any time. 
 
WHAT ARE THE COSTS TO ME/MY BABY? WILL I/MY BABY RECEIVE ANY 
PAYMENT? 
 
There are no costs to you and your baby for the study vaccine, study visits, or study procedures. 
You and your baby will not receive any form of payment to take part in this study. You and your 
baby will receive a ticket for travel and a meal ticket for coming to the study visits at no cost to 
you. 
 
WHAT HAPPENS IF I AM/MY BABY IS INJURED? 
 
If you or your baby are hurt from this study or due to the study vaccines, you or your baby will 
be taken care of with no costs to you. This care is promised by the Principal Investigator (PI) at 
the HCFMRP-USP. You will not be paid any money through the National Institute of Health 
(NIH), which is the main sponsor of this study. If necessary you will receive help for your baby’s 
health if he or she is injured during the study, for how long it is needed, as well as payment for 
these problems. The research site has insurance to cover costs.  You will not be giving up any of 
your or your baby’s legal rights by signing this consent form.  
 
WHAT ARE MY/MY BABY’S RIGHTS AS A RESEARCH SUBJECT? 
 
Taking part in this study is completely your decision. You may choose not to take part or not to 
allow your baby to take part in this study or to leave this study or take your baby out of this study 
at any time. You and your baby will be treated the same no matter what you decide. 
 
We will tell you about new information from this or other studies that may affect your and your 
baby’s health or your choice to stay in this study. Your decision will not affect whether or not 
you can be in other studies by the NICHD and will not take any of your benefits away. If you 
want the results of this study, let the study staff know. 
 
WHAT DO I DO IF I HAVE QUESTIONS OR PROBLEMS? 
 
For questions about this study or a research-related injury, contact: 
 
For questions about your and your baby’s rights as a research subject, contact: 
 

NICHD P1091 
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May 23, 2016 
 
Page 93 of 93 
SIGNATURE PAGE – NICHD P1091 
AUTHORIZATION FOR ACCESSING DATA FROM RESEARCH PARTICIPANT 
MEDICAL CHART. 
 
During your AND your baby’s participation in the study, the responsible researcher will need to 
have access to your medical data recorded in the charts. For this, we require that you also allow 
the researcher to access these data; marking the box below if this is your decision.  
 
 
I authorize the study investigator to have access to my and my baby’s medical data contained in 
the medical charts. 
( ) Yes ( ) No  
 
If you have read this consent form (or had it explained to you), all your questions have been 
answered, and you agree to be in the study and allow your baby to take part in this study, 
please sign your name below. 
 
 
 
_______________________________  _______________________________  ____________ 
 
Participant’s Name (print) 
Participant’s Name (signature) 
Date 
 
 
_______________________________  _______________________________  ____________ 
Participant’s Mother or guardian (print) 
Mother or guardian (signature) 
Date 
 
 
_______________________________  _______________________________  ____________ 
 
Father’s Name (print) 
Father’s Name (signature) 
Date 
 
(If father’s consent is required) 
(If father’s consent is required) 
 
 
_______________________________  _______________________________  ____________ 
 
Participant’s Legal Guardian (print) 
Legal Guardian’s (signature) 
Date 
 
 
_______________________________  _______________________________  ____________ 
 
Study Staff Conducting (print) 
Study Staff (signature) 
Date 
 
 
_______________________________  _______________________________  ____________ 
 
Consent Discussion (print) 
Consent Discussion (signature) 
Date 
 
 
_______________________________  _______________________________  ____________ 
 
Witness’s Name (print) 
Witness’s Name (signature) 
Date