The Interaction Between Measles and DTP Vaccination
Condition: Non-target Heterologous Effects of Vaccines; Vaccine Interactions
MeSH terms: Measles
Study type: Interventional

Summary: 
      The purpose of this study is to investigate for the broad immunological effects of
      administering measles vaccine (MV) and diphtheria-tetanus-whole cell pertussis vaccine (DTP)
      to 9 month old Gambian infants, either alone or together. Effects on vaccine-specific immune
      responses, innate immunity, and immune memory were studied. The hypothesis is that when MV
      and DTP are given together there will be more inflammation and this will interfere with
      generation of immunity to the vaccine and to other non-vaccine related stimuli.
    

Detailed description: 
      Many studies demonstrate that routine Expanded Program on Immunisation (EPI) vaccinations
      have "non-specific" or "heterologous" effects on child survival that cannot be accounted for
      by protection against the vaccine specific disease. These effects were overlooked in the past
      because it was assumed that the impact on survival would be proportional to reduction in the
      targeted infection. Large epidemiological studies in Bangladesh and Guinea-Bissau have shown
      that live vaccines, including measles vaccine (MV), have beneficial effects on overall
      mortality which cannot be explained by protection against the vaccine specific disease.
      Deleterious non-specific effects were shown convincingly in the high-titre MV trials in which
      girls, but not boys, had a two-fold increase in mortality even though the vaccine was fully
      protective against measles. A reinterpretation of these trials indicated that the most likely
      explanation was that the increased female mortality was due to inactivated vaccines provided
      after MV. It has further been shown in smaller observational studies that receiving
      diphtheria, tetanus and whole cell pertussis combined vaccine (DTwP) either with or after MV
      negates the beneficial effects of MV, and may lead to increased mortality. However, the
      increased mortality of girls in male-female twin pairs was not apparent when MV was given
      after the last dose of DTwP. In the present EPI schedule in The Gambia, DTwP is administered
      as a single dose vaccine at 2, 3 and 4 months, and MV at nine months. However, many children,
      particularly in low income countries, present late for their vaccines and may subsequently
      receive them in the wrong order. In particular DTP is often given at the wrong time point,
      e.g. the third DTP dose (DTP3) with MV. Given the increasing evidence that the order in which
      vaccines are administered is crucial, the routine practice of administering missed EPI
      vaccines at late presentation or boosting with DTP in year 2 may not be advisable.

      The mechanism behind these effects is unknown, and whether there is an immunological basis
      has yet to be explored. The majority of controlled trials of vaccine efficacy have focused on
      vaccine specific antibody (Ab) responses to test vaccine efficacy, and few studies have
      investigated T cell memory induction, despite the fact that it is likely to be critical for
      long term protection. Indeed, the cellular response to MV seems to be crucial in protecting
      against severe disease and death, and cellular responses are required to protect against
      Bordetella pertussis infection. Live vaccines such as bacillus Calmette-Guerin (BCG) and MV
      have been shown to stimulate Th1 type immune responses. The immune response to DTwP, a killed
      vaccine, tends to be Th2 biased in early life, despite the fact that the whole cell pertussis
      component biases towards a Th1 response. DTwP contains an aluminium based adjuvant, aluminium
      hydroxide, which is excellent at promoting humoral and Th2 responses, but poor at generating
      good cell mediated immunity and long term T cell memory. This polarisation of cellular
      reactivity to live and killed vaccines may explain why administering a killed vaccine with a
      live vaccine abrogates the beneficial effect of the live vaccine. Conversely, administering a
      live vaccine after DTwP may cause a shift towards protective Th1 type immunity, thus
      diminishing the harmful effects of DTwP and providing a non-specific survival benefit.
      Interestingly, aluminium hydroxide has been shown to cause enhanced susceptibility to
      tuberculosis (TB) in animal models. Thus the aluminium adjuvant in DTwP may play a role in
      the deleterious effect of DTwP on live vaccines, possibly through an influence on the
      generation of T cell memory to other infections and vaccines.

      Attributing the observed effects of the DTwP / MV interactions entirely to shifts in the T
      helper cell 1 (Th1) / Th2 profile is likely to be an over simplification, but provides a good
      starting point for unravelling this phenomenon. Other arms of the immune response that need
      to be considered are regulatory T cells (Tregs) and the Th17 inflammatory T cell lineage. The
      former are a heterogeneous group of naturally occurring and induced T cells, and have been
      shown to play a regulatory role in immunity to a number of infectious diseases, but almost
      nothing is known about their generation or functional role in vaccine immunogenicity in
      humans. Newborns are known to have high levels of functional Tregs, and these are likely to
      be essential in controlling the immune response to antigens encountered in early life, as
      well as modulating self reactive responses. Measles vaccination causes suppression of T cell
      responses, and measles vaccinated children upregulate Forkhead Box P3 (FOXP3) expression (Ota
      et al, personal communication), suggesting a role for Tregs. Thus Treg induction is likely to
      be an important component of the immune response to MV.

      This study will investigate in detail the immunological consequences of giving DTP or MV
      alone or at the same time. The study will involve an intervention trial to analyse the effect
      of giving DTP with MV on the generation of T cell memory (effector and central), humoral
      responses, pro-inflammatory cytokine profile (Th1, Th2, Th17) and Treg responses to measles
      and recall antigens. Our detailed immunological studies will provide vital immunological data
      on potential mechanisms of the DTP / MV interaction. A comprehensive understanding of the
      immunological effects of administering either DTP alone or DTP and MV simultaneously will
      help us understand why these interventions might be detrimental, and may suggest the need to
      refine current EPI practices. It is also crucial to gain a detailed understanding of the
      immunological effects of possible deleterious interactions between the current EPI vaccines,
      before introducing new vaccines that are becoming available for testing in early life e.g. TB
      and malaria vaccines. Furthermore, understanding mechanisms whereby MV provides survival
      benefits might identify strategies that can be harnessed in future vaccine design.

      All infants will be given a MV challenge at 18 months of age and immunological parameters
      will be analysed 1 month later. This will establish whether any vaccine group effects at 10
      months off age persist until 18 months of age and influence the immune response to a new
      immune challenge.

      Two primary hypotheses as detailed below will be tested as a starting point, but other
      immunological assays will be conducted. Furthermore all analyses will take sex into account
      since the heterologous effects of vaccines are different in males and females, with females
      generally being more susceptible.

      Hypotheses:

        1. DTP (a killed vaccine) drives primarily a Th2 response and MV (a live vaccine) drives
           primarily a Th1 response. A DTP driven Th2 response occurring at the time of trying to
           activate a Th1 response to MV will interfere with the priming of measles specific memory
           responses and responses to other recall antigens.

        2. The extra Th2 stimulation from DTP at the time of MV will provide too many signals to
           allow the generation of regulatory T cells (Tregs) which are an essential component of
           the immunological response to MV.
    

Intervention name(s): Measles Vaccine at 9 months of age; DTP Vaccine at 9 months of age; Measles Vaccine at 18 months of age
Intervention type(s): Biological; Biological; Biological
Intervention description(s): Single standard intramuscular (i.m.) dose of measles vaccine (MV) (Edmonston Zagreb strain, Serum Institute of India Ltd., Pune, India) into the deltoid at 9 months of age; Single intramuscular (i.m.) dose of diphtheria-tetanus-whole cell pertussis vaccine (Serum Institute of India Ltd.) into the thigh at 9 months of age; Single standard intramuscular (i.m.) dose of measles vaccine (MV) (Edmonston Zagreb strain, Serum Institute of India Ltd., Pune, India) into the deltoid at 18 months of age
Other intervention name(s): MV; DTP; MV
Intervention MeSH terms: Vaccines
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary purpose: Basic Science
Keywords: Immunity, Innate; Immunity, Non-Specific; Antibodies; Cytokines; Immunity, Cellular