Shabir A. Madhi, PhD, on How Stalk Antibodies Protect Against Influenza in Pregnant Women With HIV

As the effectiveness of the seasonal influenza virus vaccine varies depending on the strains in circulation, a research group set out to determine whether the hemagglutinin (HA) stalk antibody could potentially provide universal influenza virus protection.¹

The researchers investigated the immunoglobulin (IgG) response to the H1 HA stalk domain (H1/stalk) among 145 pregnant women with and without HIV infection who had received inactivated influenza vaccines (IIVs). The researchers were then able to evaluate the association of H1/stalk IgG and the odds for developing influenza virus illness.

Senior author Shabir A. Madhi, PhD, who is a professor of vaccinology at the University of the Witwatersrand and director of the South African Medical Research Council Respiratory and Meningeal Pathogens Research Unit, answered questions from Infectious Diseases Consultant about the findings and the future of HA stalk antibodies in influenza virus vaccines.

Infectious Diseases Consultant: What was the motivation behind your study?

Shabir Madhi: The effectiveness of current seasonal influenza vaccines is unpredictable due to possibility of mismatch between the vaccine and circulating strains of the virus. Furthermore, the mechanism of vaccine-induced protection in people living with HIV is uncertain, as there is a disconnect between modest immune responses evaluated by the HA inhibition (HAI) assay and the relatively high vaccine efficacy.

Recently, the membrane proximal HA stalk domain has been explored as a potential influenza vaccine candidate. This stalk epitope domain, though immune subdominant compared with the head domain, shows a high degree of conservation across divergent strains and undergoes limited drift under immune pressure. Stalk-specific antibodies have been shown to exhibit in-vitro cross-neutralizing activity against subtypes within the same group. This motivated our study to investigate the stalk antibody responses following a placebo-controlled trivalent IIV efficacy trial in pregnant women and evaluate the association of stalk antibodies and protection against influenza illness.

ID CON: Why did you look specifically at pregnant women with and without HIV, and how do you think that impacted the findings?

SM: We opportunistically leveraged sample sets from a randomized, placebo-controlled trial that was undertaken in pregnant women with and without HIV, on which we have previously reported on the efficacy of seasonal influenza vaccine in these women. Included in that study was the observation of the disconnect between trivalent IIV3-induced antibodies against the immunodominant HA head domain (analyzed using the HAI assay) and vaccine efficacy observed against confirmed influenza illness in women living with HIV.

Those findings, which corroborated findings from another randomized-controlled trial in adults living with HIV, suggested that protection mediated by IIV in people with HIV infection may be associated with other mediators of immunity induced by IIV vaccination.

The findings in this study suggest an association of H1/stalk antibodies with protection against A/H1N1 influenza illness. In addition, the H1/stalk antibody threshold that was associated with significant reduced odds of A/H1N1 illness was also determined. Differences were observed in correlations between post-vaccination H1/stalk antibody and HAI responses stratified by HIV; discordant among HIV-uninfected women but more aligned among HIV-infected women. We further found that post vaccination H1/stalk antibody responses in contrast to HAI responses were less interfered from the pre-existing antibodies, allowing a more favorable vaccine response to the stalk domain.

ID CON: How do you expect the results of this study to impact the effectiveness and development of seasonal influenza virus vaccines?

SM: There is limited data in humans, and especially in people living with HIV, on the role of stalk antibodies against protection from influenza illness. This study provides evidence of H1/stalk domain to be a potential influenza vaccine candidate against Group 1 influenza illness, which could be considered for further development.

Further, the study also provides correlates of protection for H1/stalk antibodies against influenza illness. Notably, the results suggest that H1/stalk antibody responses were significantly induced in both HIV-uninfected and HIV-infected women and were free of immunological cap or interference from the pre-existing stalk H1/antibodies, which forms an important underpinning in development of an effective vaccine candidate.

ID CON: What are the key takeaway messages from your study for infectious disease specialists and other health care providers?

SM: Vaccination of pregnant women with IIV3 induces modest H1/stalk antibody responses, which is associated with protection against A/H1N1 influenza illness. Such responses could be boosted by a H1/stalk vaccine, which could be an important pathway to the development of an influenza virus vaccine at least targeted at Group 1 influenza virus that is less sensitive to genetic drift of the virus in protecting against influenza illness.

Reference:

1. Dhar N, Kwatra G, Nunes MC, et al. Hemagglutinin stalk antibody responses following trivalent inactivated influenza vaccine immunization of pregnant women and association with protection from influenza virus illness. September 27, 2019. Clinical Infectious Diseases, Volume 71, Issue 4, 15 August 2020, Pages 1072–1079. Doi: 10.1093/cid/ciz927