Immunogenicity and Safety of Different Dosing Schedules of Trivalent Influenza Vaccine in HIV-infected Pregnant Women: a Randomized Controlled Trial

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.