Humoral correlates of protection against influenza A H3N2 virus infection

Gregory Hoy; Daniel Stadlbauer; Angel Balmaseda; Guillermina Kuan; Roger López; Juan Manuel Carreno Quiroz; Sergio Ojeda; Nery Sánchez; Temima Yellin; Miguel Plazaola; Aaron Frutos; Florian Krammer; Aubree Gordon

doi:10.1093/infdis/jiae258

Humoral correlates of protection against influenza A H3N2 virus infection

J Infect Dis. 2024 May 9:jiae258. doi: 10.1093/infdis/jiae258. Online ahead of print.

Authors

Gregory Hoy¹, Daniel Stadlbauer², Angel Balmaseda^{3

4}, Guillermina Kuan^{3

5}, Roger López^{3

4}, Juan Manuel Carreno Quiroz², Sergio Ojeda³, Nery Sánchez³, Temima Yellin², Miguel Plazaola³, Aaron Frutos¹, Florian Krammer^{2

6

7

8}, Aubree Gordon¹

Affiliations

¹ School of Public Health, University of Michigan, Ann Arbor, Michigan, USA.
² Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
³ Sustainable Sciences Institute, Managua, Nicaragua.
⁴ Laboratorio Nacional de Virología, Centro Nacional de Diagnóstico y Referencia, Ministry of Health, Managua, Nicaragua.
⁵ Centro de Salud Sócrates Flores Vivas, Ministry of Health, Managua, Nicaragua.
⁶ Center for Vaccine Research and Pandemic Preparedness (C-VaRPP), Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁷ Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁸ Ignaz Semmelweis Institute, Interuniversity Institute for Infection Research, Medical University of Vienna, Vienna, Austria.

PMID: 38723107
DOI: 10.1093/infdis/jiae258

Abstract

Background: Influenza virus remains a threat to human health, but gaps remain in our knowledge of the humoral correlates of protection against influenza virus A/H3N2, limiting our ability to generate effective, broadly protective vaccines. The role of antibodies against the hemagglutinin (HA) stalk, a highly conserved but immunologically sub-dominant region, has not been established for influenza virus A/H3N2.

Methods: Household transmission studies were conducted in Managua, Nicaragua across three influenza seasons. Household contacts were tested for influenza virus infection using RT-PCR. We compared pre-existing antibody levels against full-length hemagglutinin (FLHA), HA stalk, and neuraminidase (NA) measured by enzyme-linked immunosorbent assay (ELISA), along with HA inhibition assay (HAI) titers, between infected and uninfected participants.

Results: A total of 899 individuals participated in household activation, with 329 infections occurring. A four-fold increase in initial HA stalk titers was independently associated with an 18% decrease in the risk of infection (OR=0.82, 95%CI 0.68-0.98, p=0.04). In adults, anti-HA stalk antibodies were independently associated with protection (OR=0.72, 95%CI 0.54-0.95, p=0.02). However, in 0-14-year-olds, anti-NA antibodies (OR=0.67, 95%CI 0.53-0.85, p<0.01) were associated with protection against infection, but anti-HA stalk antibodies were not.

Conclusions: The HA stalk is an independent correlate of protection against A/H3N2 infection, though this association is age dependent. Our results support the continued exploration of the HA stalk as a target for broadly protective influenza vaccines but suggest that the relative benefits may depend on age and influenza virus exposure history.

Keywords: correlates of protection; global health; influenza; vaccination.

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