Evaluation of correlates of protection against influenza A(H3N2) and A(H1N1)pdm09 infection: Applications to the hospitalized patient population

Petrie, Joshua G.; Martin, Emily T.; Truscon, Rachel; Johnson, Emileigh; Cheng, Caroline; McSpadden, EJ; Malosh, Ryan E.; Lauring, Adam S.; Lamerato, Lois; Eichelberger, Maryna C.; Ferdinands, Jill; Monto, Arnold S.

doi:10.1101/416628

Cited by 5 publications

(10 citation statements)

References 25 publications

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“…Adults hospitalized at the University of Michigan Hospital (Ann Arbor, MI, USA) or Henry Ford Hospital (Detroit, MI, USA) were enrolled according to a case definition of within ≤10 days of acute respiratory illness onset and subsequently tested for influenza by reverse transcription-PCR (RT-PCR). Serum specimens collected at hospital admission were obtained for estimation of preinfection/early infection antibodies; 58% of specimens included in this analysis were collected within 3 days of illness onset (42). We analyzed serum samples from 62 hospitalized individuals that had PCR-confirmed H1N1 influenza virus infections.…”

Section: Resultsmentioning

confidence: 99%

Assessing the Protective Potential of H1N1 Influenza Virus Hemagglutinin Head and Stalk Antibodies in Humans

Christensen

Toulmin

Griesman

et al. 2019

J Virol

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Seasonal influenza viruses are a major cause of human disease worldwide. Most neutralizing antibodies (Abs) elicited by influenza viruses target the head domain of the hemagglutinin (HA) protein. Anti-HA head Abs can be highly potent, but they have limited breadth since the HA head is variable. There is great interest in developing new universal immunization strategies that elicit broadly neutralizing Abs against conserved regions of HA, such as the stalk domain. Although HA stalk Abs can provide protection in animal models, it is unknown if they are present at sufficient levels in humans to provide protection against naturally acquired influenza virus infections. Here, we quantified H1N1 HA head- and stalk-specific Abs in 179 adults hospitalized during the 2015–2016 influenza virus season. We found that HA head Abs, as measured by hemagglutinin inhibition (HAI) assays, were associated with protection against naturally acquired H1N1 infection. HA stalk-specific serum total IgG titers were also associated with protection, but this association was attenuated and not statistically significant after adjustment for HA head-specific Ab titers. We found slightly higher titers of HA stalk-specific IgG1 and IgA Abs in sera from uninfected participants than in sera from infected participants; however, we found no difference in serumin vitroantibody-dependent cellular cytotoxicity activity. In passive transfer experiments, sera from participants with high HAI activity efficiently protected mice, while sera with low HAI activity protected mice to a lower extent. Our data suggest that HA head Abs are more efficient at protecting against H1N1 infection than HA stalk Abs.IMPORTANCEAbs targeting the HA head of influenza viruses are often associated with protection from influenza virus infections. These Abs typically have limited breadth, since mutations frequently arise in HA head epitopes. New vaccines targeting the more conserved HA stalk domain are being developed. Abs that target the HA stalk are protective in animal models, but it is unknown if these Abs exist at protective levels in humans. Here, we completed experiments to determine if Abs against the HA head and stalk were associated with protection from naturally acquired human influenza virus infections during the 2015–2016 influenza season.

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Section: Resultsmentioning

confidence: 99%

Assessing the Protective Potential of H1N1 Influenza Virus Hemagglutinin Head and Stalk Antibodies in Humans

Christensen

Toulmin

Griesman

et al. 2019

J Virol

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show abstract

“…Adults hospitalized at the University of Michigan Hospital (Ann Arbor, MI, USA) or Henry Ford Hospital (Detroit, MI, USA) were enrolled according to a case definition of within ≤10 days of acute respiratory illness onset and subsequently tested for influenza by RT-PCR. Serum specimens collected at hospital admission were obtained for estimation of pre/early-infection antibodies; 58% of specimens included in this analysis were collected within 3 days of illness onset (41). We analyzed serum samples from 62 hospitalized individuals that had PCR-confirmed H1N1 influenza virus infections.…”

Section: Resultsmentioning

confidence: 99%

“…If our infected participants were making de novo Abs responses, we would anticipate that some of them would have high HAI titers to the infecting H1N1 virus. In addition, Ab titers do not typically increase as days from symptom onset to blood specimen collection increases (41), which suggests that samples used in this study were collected prior to the generation of de novo Ab responses against the infecting virus.…”

Section: Discussionmentioning

confidence: 99%

Assessing the protective potential of H1N1 influenza virus hemagglutinin head and stalk antibodies in humans

Christensen

Toulmin

Griesman

et al. 2018

Preprint

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23Seasonal influenza viruses are a major cause of human disease worldwide. Most 24 neutralizing antibodies (Abs) elicited by influenza viruses target the head domain of the 25 hemagglutinin (HA) protein. Anti-HA head Abs can be highly potent, but they have 26 limited breadth since the HA head is variable. There is great interest in developing new 27 universal immunization strategies that elicit broadly neutralizing Abs against conserved 28 regions of HA, such as the stalk domain. Although HA stalk Abs can provide protection 29 in animal models, it is unknown if they are present at sufficient levels in humans to 30 provide protection against naturally-acquired influenza virus infections. Here, we 31 quantified H1N1 HA head and stalk-specific Abs in 179 adults hospitalized during the 32 2015-2016 influenza virus season. We found that HA head Abs, as measured by 33 hemagglutinin-inhibition (HAI) assays, were associated with protection against naturally-34 acquired H1N1 infection. HA stalk-specific serum total IgG titers were also associated 35 with protection, but this association was slightly attenuated and not statistically 36 significant after adjustment for HA head-specific Ab titers. We found higher titers of HA 37 stalk-specific IgG1 and IgA Abs in sera from uninfected participants than from infected 38 participants; however, we found no difference in sera in vitro antibody dependent 39 cellular cytotoxicity activity. In passive transfer experiments, sera from participants with 40 high HAI activity efficiently protected mice, while sera with low HAI activity protected 41 mice to a lower extent. Our data suggest that human HA head and stalk Abs both 42 contribute to protection against H1N1 infection. 43 44 45 3 Importance 46Abs targeting the HA head of influenza viruses are often associated with protection from 47 influenza virus infections. These Abs typically have limited breadth since mutations 48 frequently arise in HA head epitopes. New vaccines targeting the more conserved HA 49 stalk domain are being developed. Abs that target the HA stalk are protective in animal 50 models, but it is unknown if these Abs exist at protective levels in humans. Here, we 51 found that Abs against both the HA head and HA stalk were associated with protection 52 from naturally-acquired human influenza virus infections during the 2015-2016 influenza 53 season.

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“…A lack of association between anti-neuraminidase antibody-mediated immunity and protection 271 could explain, in part, the high incidence of infection during the 2017-2018 influenza season. We have 272 previously demonstrated that anti-neuraminidase antibody was not associated with protection during 273 the 2014-2015 season, which was also characterized by high incidence of influenza A(H3N2) infections 274 [26]. Although neuraminidase content is not standardized in influenza vaccines, we observed that anti-275 neuraminidase antibody titers were higher among vaccinated individuals suggesting that some of the 276 existing anti-neuraminidase antibody in this population resulted from vaccination.…”

Section: Discussion 234mentioning

confidence: 84%

“…The serum specimens in this study were collected at a single time point early during acute illness [26]. 295…”

Section: Discussion 234mentioning

confidence: 99%

Antibodies against egg- and cell-grown influenza A(H3N2) viruses in adults hospitalized during the 2017-2018 season

Levine

Martin

Petrie

et al. 2018

Preprint

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BackgroundThe 2017-2018 US influenza season was severe with low vaccine effectiveness. Circulating A(H3N2) viruses from multiple genetic groups were antigenically similar to cell-grown vaccine strains. However, most influenza vaccines are egg-propagated.MethodsSerum was collected shortly after illness onset from 15 PCR confirmed A(H3N2) infected cases and 15 uninfected (controls) hospitalized adults enrolled in an influenza vaccine effectiveness study.Geometric mean titers against egg- and cell-grown A/Hong Kong/4801/2014 A(H3N2) vaccine strains and representative circulating viruses (including A/Washington/16/2017) were determined by microneutralization (MN) assays. Independent effects of strain-specific titers on susceptibility were estimated by logistic regression.ResultsMN titers against egg-A/Hong Kong were significantly higher among those who were vaccinated (MN GMT: 173 vs 41; P = 0.01). However, antibody titers to cell-grown viruses were much lower in all individuals (P>0.05) regardless of vaccination. In unadjusted models, a 2-fold increase in MN titers against egg-A/Hong Kong was not significantly protective against infection (29% reduction; p=0.09), but a similar increase in cell-A/Washington titer (3C.2a2) was protective (60% reduction; p=0.02). A similar increase in egg-A/Hong Kong titer was not significantly associated with odds of infection when adjusting for MN titers against A/Washington (15% reduction; P=0.61). A 54% reduction of odds of infection was observed with a 2-fold increase in A/Washington (not significant; P=0.07), adjusted for egg-A/Hong Kong titer.ConclusionAlthough individuals vaccinated in 2017-2018 had high antibody titers against the egg-adapted vaccine strain, antibody responses to cell-grown circulating viruses may not be sufficient to provide protection, likely due to egg-adaptation in the vaccine.

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Evaluation of correlates of protection against influenza A(H3N2) and A(H1N1)pdm09 infection: Applications to the hospitalized patient population

Cited by 5 publications

References 25 publications

Assessing the Protective Potential of H1N1 Influenza Virus Hemagglutinin Head and Stalk Antibodies in Humans

Assessing the Protective Potential of H1N1 Influenza Virus Hemagglutinin Head and Stalk Antibodies in Humans

Assessing the protective potential of H1N1 influenza virus hemagglutinin head and stalk antibodies in humans

Antibodies against egg- and cell-grown influenza A(H3N2) viruses in adults hospitalized during the 2017-2018 season

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