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Dissecting the hemagglutinin head and stalk-specific IgG antibody response in healthcare workers following pandemic H1N1 vaccination.

ABSTRACT: Traditionally, neutralising antibodies that are directed to the major surface glycoprotein hemagglutinin (HA) head domain are measured as surrogate correlates of protection against influenza. In addition to neutralization, hemagglutinin-specific antibodies may provide protection by mediating antibody-dependent cellular cytotoxicity (ADCC). During the 2009 pandemic, vaccination induced HA-specific antibodies that were mostly directed to the conserved HA stalk domain. However, the protective role of these antibodies has not been investigated in detail. We quantified the HA head and stalk-specific antibodies, their avidity, ability to neutralise virus and activate natural killer cells in an ADCC assay. We analyzed sera obtained from 14 healthcare workers who had low hemagglutination inhibition (HI) antibody titres at 3 months after pandemic H1N1 vaccination as well as from 22 controls. Vaccination resulted in a HA stalk dominant antibody response in both low responders and controls. Revaccination of low responders, 5 months later, resulted in a boost in antibodies, with HA head-specific antibodies dominating the response. Comparative analysis of head and stalk antibody avidities revealed that stalk-specific antibodies were qualitatively superior. Furthermore, stalk-specific antibodies mediated virus neutralization and had significantly higher ADCC activity than head-specific antibodies. Despite the head and stalk-specific antibodies being lower in low responders, they had comparable antibody avidity, ADCC functionality and neutralising capacity to those of controls who had high HI titres post-vaccination. Thus, our study has demonstrated that HA stalk-specific antibodies may have an important role in protection through neutralization and ADCC in low responders who do not maintain seroprotective HI antibodies.

SUBMITTER: Tete SM

PROVIDER: S-EPMC5707877 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Dissecting the hemagglutinin head and stalk-specific IgG antibody response in healthcare workers following pandemic H1N1 vaccination.

Tete Sarah M SM Krammer Florian F Lartey Sarah S Bredholt Geir G Wood John J Skrede Steinar S Cox Rebecca J RJ

NPJ vaccines 20160728

Traditionally, neutralising antibodies that are directed to the major surface glycoprotein hemagglutinin (HA) head domain are measured as surrogate correlates of protection against influenza. In addition to neutralization, hemagglutinin-specific antibodies may provide protection by mediating antibody-dependent cellular cytotoxicity (ADCC). During the 2009 pandemic, vaccination induced HA-specific antibodies that were mostly directed to the conserved HA stalk domain. However, the protective role ...[more]

PMID: 29250435

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Project description:IntroductionA novel H1N1 vaccine was manufactured in response to the pandemic in 2009. This study describes the willingness to be vaccinated for H1N1 among healthcare workers (HCWs) in primary healthcare clinics with and without chronic medical conditions, their reasons for refusing vaccination and whether they sought additional information to make an informed decision for the vaccination.Materials and methodsAn anonymous survey was conducted in November 2009 among all medical, nursing, allied health and operations HCWs in nine primary care clinics in Singapore. Participants were asked if they had any chronic medical conditions associated with influenza-related complications (example: asthma, stroke, heart disease, cancer, diabetes mellitus, renal disease), their perception towards vaccination for H1N1 and against seasonal influenza within the preceding 2 years.ResultsThe initial response rate was 80%, of which 711 (54.7%) of the completed surveys were analysed. Among the 711 respondents, 16.6% reported having at least 1 chronic disease. Asthma (10.8%), hypertension (10.4%) and dyslipidaemia (9.8%) were the main chronic conditions. Only 39.4% of respondents were willing to be vaccinated against H1N1. Males were 2.07 (95% CI 1.19-3.62) times more likely than females to receive the H1N1 vaccination; the 45-54 and 55+ years old were 2.12 (95% CI 1.06-4.24) and 2.44 (95% CI 1.13-5.27) times more willing than those below 25 years old; and those who considered accepting the seasonal influenza vaccine were 7.0 times more likely than those who did not (95%CI 4.48-10.92). The 2 principal barriers were "fear of side effects" and "unsure of vaccine's effectiveness". Although 78% attended some H1N1-related talks, only 7% of all HCWs felt that they had sufficient information. Most wanted more information about the vaccine's safety profile and contraindications.ConclusionFewer than 40% of HCWs expressed willingness to receive the H1N1 vaccination, lower than past rates of influenza vaccine. HCWs in primary care clinics who had a chronic condition did not perceive themselves to be at higher risk of developing H1N1-related complications and were not more willing than the rest of the HCWs to accept H1N1 vaccination. Vaccine's side effects and effectiveness were the main concerns. Uptake of H1N1 vaccine may improve with targeted health information covering the vaccine's safety profile.

Project description:IntroductionFollowing the coronavirus disease 19 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection, vaccination became the main strategy against disease severity and even death. Healthcare workers were considered high-risk for infection and, thus, were prioritised for vaccination.MethodsA follow-up to a SARS-CoV-2 seroprevalence study among clinical and non-clinical HCWs at the Aga Khan University Hospital, Nairobi, we assessed how vaccination influenced SARS-CoV-2 anti-spike IgG antibody responses and kinetics. Blood samples were drawn at two points spanning 6 to 18 months post-vaccination, and SARS-CoV-2 spike antibody levels were determined by enzyme-linked immunosorbent assay.ResultsAlmost all participants, 98% (961/981), received a second vaccine dose, and only 8.5% (83/981) received a third dose. SARS-CoV-2 spike IgG antibodies were detected in 100% (961/961) and 92.7% (707/762) of participants who received two vaccine doses, with the first and second post-vaccine test, respectively, and in 100% (83/83) and 91.4% (64/70) of those who received three vaccine doses at the first and second post-vaccine test, respectively. Seventy-six participants developed mild infections, not requiring hospitalisation even after receiving primary vaccination. Receiving three vaccine doses influenced the anti-spike S/Co at both the first (p<0.001) and second post-vaccination testing (p<0.001). Of those who tested SARS-CoV-2 positive, the anti-spike S/Co ratio was significantly higher than those who were seronegative at the first post-vaccine test (p = 0.001). Side effects were reported by almost half of those who received the first dose, 47.3% (464/981), 28.9% (278/961) and 25.3% (21/83) of those who received the second and third vaccine doses, respectively.Discussion and conclusionFollowing the second dose of primary vaccination, all participants had detectable anti-spike antibodies. The observed mild breakthrough infections may have been due to emerging SARS-CoV-2 variants. Findings suggest that although protective antibodies are induced, vaccination protected against COVID-19 disease severity and not necessarily infection.

Project description:The limited ability of current influenza virus vaccines to protect from antigenically drifted or shifted viruses creates a public health problem that has led to the need to develop effective, broadly protective vaccines. While current influenza virus vaccines mostly induce an immune response against the immunodominant and variable head domain of the hemagglutinin, the major surface glycoprotein of the virus, the hemagglutinin stalk domain has been identified to harbor neutralizing B-cell epitopes that are conserved among and even between influenza A virus subtypes. A complete understanding of the differences in evolution between the main target of current vaccines and this more conserved stalk region are missing. Here, we performed an evolutionary analysis of the stalk domains of the hemagglutinin of pre-pandemic seasonal H1N1, pandemic H1N1, seasonal H3N2, and influenza B viruses and show quantitatively for the first time that the stalk domain is evolving at a rate that is significantly slower than that of the head domain. Additionally, we found that the cross-reactive epitopes in the stalk domain targeted by broadly neutralizing monoclonal antibodies are evolving at an even slower rate compared to the full head and stalk regions of the protein. Finally, a fixed-effects likelihood selection analysis was performed for these virus groups in both the head and stalk domains. While several positive selection sites were found in the head domain, only a single site in the stalk domain of pre-pandemic seasonal H1 hemagglutinin was identified at amino acid position 468 (H1 numbering from methionine). This site is not located in or close to the epitopes of cross-reactive anti-stalk monoclonal antibodies. Furthermore, we found that changes in this site do not significantly impact virus binding or neutralization by human anti-stalk antibodies, suggesting that some positive selection in the stalk domain is independent of immune pressures. We conclude that, while the stalk domain does evolve over time, this evolution is slow and, historically, is not directed to aid in evading neutralizing antibody responses.

Dataset Information

Dissecting the hemagglutinin head and stalk-specific IgG antibody response in healthcare workers following pandemic H1N1 vaccination.

Publications

Dissecting the hemagglutinin head and stalk-specific IgG antibody response in healthcare workers following pandemic H1N1 vaccination.

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