Immunogenicity and Safety of Different Dosing Schedules of Trivalent Influenza Vaccine in HIV-infected Pregnant Women
Condition: Influenza
MeSH terms: Influenza, Human
Study type: Interventional
Phase: Phase 3

Summary: 
      The overall aim of this project is to evaluate the safety and immunogenicity of 3 different
      dosing options of trivalent influenza vaccine (TIV) vaccination of HIV-infected pregnant
      women: single dose, double dose (at same time point) and two-doses (1 month apart).
    

Detailed description: 
      Determining the contribution of influenza to early childhood morbidity and mortality in
      sub-Saharan Africa and the potential to prevent influenza disease through vaccination may
      contribute to reducing childhood deaths; since influenza illness is a vaccine preventable
      disease for which vaccines are developed, licensed and available at reasonable cost.
      Unfortunately, infants at highest risk for serious disease are those under 6 months of age,
      for whom trivalent inactivated influenza vaccine (TIV) is poorly immunogenic and not
      licensed. As pregnant women also have an increased risk of serious illness (3.3-5.5 fold for
      hospitalization for influenza-associated acute cardio-respiratory illness) from influenza
      infection, one strategy to prevent the complications of influenza in pregnant women and young
      infants is through maternal TIV immunization, which is recommended by the WHO. This could
      result in direct protection of the women and protection of the young infant consequent to
      transplacental transfer of TIV induced antibody.

      Barriers to administration of vaccines during pregnancy including lack of information on
      effectiveness and concerns about safety probably explain the virtual non-existent use of TIV
      in pregnant women from low-middle income countries, including South Africa. Although there
      was a national campaign for influenza vaccination of pregnant women in South Africa during
      2010 due to the concern of continued circulation of H1N1-2009pdm influenza virus, the uptake
      of vaccine remains poor. TIV immunization of pregnant women is still not provided as standard
      of care to pregnant women attending antenatal-clinics in South Africa, in part because of
      absence of any data from any African setting with regard to its risk-benefit ratio.

      The immunogenicity and efficacy of TIV in HIV-infected adults was only recently documented in
      an African setting. This placebo-controlled, community-based randomized, placebo controlled
      trial, conducted at Themba Lethu HIV clinic, Helen Joseph hospital, reported that TIV was
      associated with a 75% reduction in influenza-confirmed illness. The results of the study also
      confirmed the safety of TIV among African HIV-infected adults. The study, however, only
      included 7 women who were pregnant. In addition to no differences in solicited adverse event
      rates, there was also no difference in either cluster of differentiation 4 (CD4+) cell count
      changes or HIV viral control in those on antiretroviral treatment between TIV vaccinees
      compared to placebo recipients. This allayed previous concerns regarding the potential
      negative effect of TIV which centered around the observed transient increase in HIV-1 viral
      load, even in HIV infected individuals on ART and who were virologically suppressed (viral
      load <400 copies/ml). Decreases in CD4+ lymphocyte counts have also been observed in
      HIV-infected individuals post TIV vaccination. These changes, however, even in past studies
      were infrequent (4-18%) and resolved at later time-points and were considered to be
      clinically non-significant.

      Only recently has data become available from another low-income country (Bangladesh) in which
      the benefit of maternal TIV vaccination was demonstrated by a 63% (95% confidence interval
      (CI) 5 to 85) reduction in laboratory-confirmed influenza illness in infants under 24 weeks
      of age in children born to mothers vaccinated with TIV and a 36% reduction in clinical
      illness in vaccinated mothers. There has, however, not been any study on the effectiveness of
      maternal immunization with TIV on influenza- associated morbidity and mortality either in the
      mothers or infants in African settings.

      Much of influenza virus associated morbidity and mortality may be due to the synergistic
      lethality of influenza with bacterial pathogens leading to pneumonia as well as other viral
      co-infections. Superimposed bacterial infections, especially Streptococcus pneumoniae and in
      patients treated with antibiotics, Staphylococcus aureus, contribute to a large proportion
      (28-65%) of pneumonia deaths associated with influenza illness during pandemics. Unpublished
      data from the Bangladeshi study show that infants of mothers who received TIV (with
      pneumococcal conjugate vaccine, 7 valent (PCV7) given to infants) were better protected from
      acquisition of pneumococcal carriage during influenza season than infants of TIV-unimmunized
      mothers. No data in the African setting are available to support or refute this observation
      from Bangladesh. As introduction of pneumococcal conjugate vaccines (PCV) in low-income
      countries is a priority of the Global Alliance for Vaccines and Immunization (GAVI), with 7
      African countries already approved, and many others to follow, to introduce PCV within the
      next five years.

      Despite the encouraging results on maternal immunization from Bangladesh, and the preliminary
      data supporting that TIV is efficacious mainly in HIV-infected non-pregnant adults, further
      data are needed to advocate for routine use of TIV during pregnancy in settings with a high
      prevalence of HIV. Reasons for this include that the impact of maternal HIV on the kinetics
      of TIV induced transplacental antibody transfer cannot be derived from available data. This
      is important as the primary focus of this proposal, and major potential public health benefit
      of maternal TIV vaccination, is targeted at protection of young infants. HIV infection is
      known to decrease placental integrity and lower antibody levels in the fetus and newborn.
      Furthermore, maternal hypergamma-globulinemia that is characteristic of HIV-infection may be
      associated with decreased neonatal antibody levels. This paradox is explained by the limited
      number of placental antibody receptors, resulting in immunoglobulin G (IgG) antibodies
      competing for available receptors and thereby decreasing vaccine-specific antibody transport.
      Preterm birth increases with HIV, chronic maternal disease or malnutrition. Transfer of
      maternal antibody which is gestational age dependant, may be more affected by maternal
      immunization in sub-Saharan Africa where these conditions are common.

      In 2011, two Maternal influenza vaccination trials are being conducted in pregnant women from
      the Soweto community, one in HIV-infected women, and the other in HIV-uninfected women. In
      both these trials (HREC reference number 101106 and 101107) the immunogenicity of a single
      dose of TIV administered between 20 and 36 weeks of gestation was investigated.

      HIV-uninfected women showed a good response one month post vaccination with 85.3%, 92.7% and
      98.5% of women having seroprotective levels of antibodies to the vaccine strains, H3N2, H1N1
      and B respectively, however, HIV-infected women showed an inferior response to vaccination.
      The CD4+ cell count at baseline (prior to vaccination) affected the immunological response
      mounted by HIV-infected women: 12.5%, 12.5% and 62.5% of women with CD4+ cell count <200, and
      50%, 66.7% and 77.8% of women with CD4+ count ≥500 had seroprotective levels to vaccine
      strains, H3N2, H1N1 and B respectively, one month post receipt of single-dose TIV.

      The overall aim of this project is to evaluate the safety and immunogenicity of 3 different
      dosing options of TIV vaccination of HIV-infected pregnant women: single dose, double dose
      (at same time point) and two-doses (1 month apart)
    

Intervention name(s): Trivalent influenza vaccine (seasonal); Normal saline
Intervention type(s): Biological; Biological
Intervention description(s): Single 0.5ml dose of Southern hemisphere 2012 TIV, formulation containing:
An A/California/7/2009 (H1N1)pdm-like virus
An A/Perth/16/2009 (H3N2)-like virus*
A B/Brisbane/60/2008-like virus * A/Wisconsin/15/2009 and A/Victoria/210/2009 are A/Perth/16/2009-like viruses for use in the 2012 Southern Hemisphere winter. This vaccine is the same as the vaccine used for the 2011 Southern hemisphere influenza season.; 0.5ml normal saline will be used as 'placebo' vaccine to maintain blinding
Other intervention name(s): Vaxigrip; NaCl
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Prevention