Contribution of Serologic Assays in the Evaluation of Influenza Virus Infection Rates and Vaccine Efficacy in Pregnant Women: Report From Randomized Controlled Trials

Clinical Infectious Diseases, Jun 2017

The utility of serologic testing to evaluate vaccine efficacy of seasonal inactivated influenza vaccine (IIV) is controversial. We aimed to evaluate the efficacy of IIV against serologically diagnosed influenza infection (SDI) and reverse-transcription polymerase chain reaction–confirmed influenza illness (PCR-CI) in women vaccinated during pregnancy.

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Contribution of Serologic Assays in the Evaluation of Influenza Virus Infection Rates and Vaccine Efficacy in Pregnant Women: Report From Randomized Controlled Trials

Abstract Background. The utility of serologic testing to evaluate vaccine efficacy of seasonal inactivated influenza vaccine (IIV) is controversial. We aimed to evaluate the efficacy of IIV against serologically diagnosed influenza infection (SDI) and reverse-transcription polymerase chain reaction–confirmed influenza illness (PCR-CI) in women vaccinated during pregnancy. Methods. We undertook a post hoc analysis of 2 randomized clinical trials evaluating IIV efficacy among human immunodeficiency virus (HIV)–uninfected and HIV-infected pregnant women. SDI was defined as ≥4-fold increase in paired hemagglutinin antibody inhibition titers from 1 month postvaccination until end-of-study participation. PCR-CI was defined as molecular diagnostic evidence of influenza virus in pharyngeal specimens collected during clinical illness. Results. Among placebo recipients, the respective incidence of PCR-CI and SDI was 5.6% and 35.0% in HIV-uninfected women and 20.5% and 43.6% among HIV-infected women. Vaccine efficacy in HIV-uninfected women was similar for PCR-CI (66.9%; 95% confidence interval [CI], –20.1% to 90.9%) and SDI (59.2%; 95% CI, 37.0%–73.5%); however, fewer women required vaccination to prevent 1 episode of SDI (5; 95% CI, 3–9) than PCR-CI (27; 95% CI, 12–∞). Also, vaccine efficacy was similar for PCR-CI (61.2%; 95% CI, 10.7%–83.2%) and SDI (60.9%; 95% CI, 33.9%–76.9%) in HIV-infected women, with 2-fold fewer women needing to be vaccinated to prevent SDI (4; 95% CI, 3–8) than PCR-CI (8; 95% CI, 4–52). Conclusions. Although vaccine efficacy was similar when measured for PCR-CI or SDI, IIV vaccination prevented a greater number of SDI than PCR-CI; the clinical relevance of the former warrants interrogation.Clinical Trials Registration. NCT01306669 and NCT01306682 influenza vaccine, efficacy, phase III trial, immunogenicity, hemagglutination inhibition assay. Vaccination of pregnant women with seasonal trivalent inactivated influenza vaccine (IIV) is efficacious against influenza illness [1–3]. Vaccine efficacy against reverse-transcription polymerase chain reaction (RT-PCR)–confirmed influenza illness (PCR-CI) was 50% in human immunodeficiency virus (HIV)–uninfected women and 58% in HIV-infected women in a randomized controlled trial in South Africa, among whom the attack rate of PCR-CI was 4% and 17% in the respective placebo recipients [2]. Vaccination of pregnant women with IIV also protected their young infants (<6 months of age) against laboratory-confirmed influenza illness [1–6]. Although paired hemagglutination antibody inhibition (HAI) assays have been used in some studies to evaluate IIV effectiveness, the utility thereof in this context has been controversial since the 1960s [7–9]. Of concern is that serology as a measure of influenza virus infection could overestimate vaccine effectiveness, due to the high HAI titers induced by vaccination in IIV recipients, resulting in them being less likely to elicit a further 4-fold increase in titers following influenza virus infection (23%) compared with IIV-unvaccinated individuals (90%) [7]. Furthermore, serologically diagnosed influenza virus infection (SDI) may not necessarily manifest as a clinical illness and therefore might not represent an outcome of public health importance. Nevertheless, it could yield a better estimate of influenza virus exposure, which may be important to ascertain. For example, the magnitude of exposure of the fetus in utero to maternal influenza virus infection could affect influenza-associated adverse pregnancy outcomes such as prematurity or low birth weight [10, 11]. We report on a post hoc objective of a efficacy trial of IIV in separate cohorts of HIV-uninfected and HIV-infected pregnant women up to 24 weeks postpartum. Specifically, we evaluated the efficacy of IIV vaccination of pregnant women and the number needed to treat (NNT) against PCR-CI and/or SDI. METHODS Details of the study cohorts in the 2 double-blind, randomized, placebo-controlled trials among HIV-infected and HIV-uninfected pregnant women, including the inclusion and exclusion criteria, have been published previously [2]. In brief, a cohort of 198 HIV-infected pregnant women was enrolled from 3 March to 2 June 2011, and 2 distinct cohorts of HIV-uninfected pregnant women were enrolled in 2011 (n = 1060) and in 2012 (n = 1056) at approximately 20–36 weeks of gestational age. While all HIV-infected women were included in an immunogenicity study on vaccine response and antibody kinetics, only a subset of HIV-uninfected women were included in the immunogenicity studies among the cohorts enrolled from 3 March to 24 June 2011 (n = 193) and 6 March to 11 June 2012 (n = 183). The women were randomized 1:1 to receive IIV or saline placebo. The influenza vaccine (Vaxigrip, lot number G05831 in 2011 and H7221-2 in 2012; Sanofi Pasteur, Lyon France) was commercially procured and was composed of the World Health Organization–recommended Southern H (...truncated)


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Madhi, Shabir A., Nunes, Marta C., Weinberg, Adriana, Kuwanda, Locadiah, Hugo, Andrea, Jones, Stephanie, van Niekerk, Nadia, Ortiz, Justin R., Neuzil, Kathleen M., Klugman, Keith P., Simões, Eric A. F., Cutland, Clare L.. Contribution of Serologic Assays in the Evaluation of Influenza Virus Infection Rates and Vaccine Efficacy in Pregnant Women: Report From Randomized Controlled Trials, Clinical Infectious Diseases, 2017, pp. 1773-1779, Volume 64, Issue 12, DOI: 10.1093/cid/cix241