Sex-specific effects of aging on the humoral immune response to repeat vaccination with the high-dose seasonal influenza vaccine in older adults

Older adults ([≥]65 years of age) bear a significant burden of severe disease and mortality associated with influenza, despite relatively high annual vaccination coverage and substantial pre-existing immunity to influenza. To test the hypothesis that host factors, including age and sex, play a role in determining the effect of repeat vaccination and levels of pre-existing humoral immunity to influenza, we evaluated pre- and post-vaccination strain-specific hemagglutination inhibition (HAI) titers in adults over 75 years of age who received a high-dose influenza vaccine in at least four out of six influenza seasons (NCT02200276). Neither age, sex, body mass index, frailty, nor repeat vaccination were significantly associated with post-vaccination HAI titer outcomes. Pre-vaccination titers, however, were significantly predictive of post-vaccination outcomes. Pre-vaccination titers to H1N1 remained constant with age, while those to H3N2 and influenza B decreased substantially with age in males but not in females. Our findings highlight the importance of pre-existing immunity in this highly vaccinated older adult population and suggest that older males are particularly vulnerable to reduced pre-existing humoral immunity to influenza from previous annual vaccination.

[1]  Henry A. Utset,et al.  B Cell Responses against Influenza Viruses: Short-Lived Humoral Immunity against a Life-Long Threat , 2021, Viruses.

[2]  M. Russell,et al.  A multisite study of pertussis vaccine effectiveness by time since last vaccine dose from three Canadian provinces: A Canadian Immunization Research Network study. , 2021, Vaccine.

[3]  S. Klein,et al.  Stop ‘controlling’ for sex and gender in global health research , 2021, BMJ Global Health.

[4]  S. Klein,et al.  Sex-specific effects of age and body mass index on antibody responses to seasonal influenza vaccines in healthcare workers. , 2021, Vaccine.

[5]  S. Klein,et al.  COVID-19: use intersectional analyses to close gaps in outcomes and vaccination , 2021, Nature.

[6]  J. Alcorn,et al.  The impact of physical frailty on the response to inactivated influenza vaccine in older adults , 2020, Aging.

[7]  R. Kennedy,et al.  Durability of humoral immune responses to rubella following MMR vaccination. , 2020, Vaccine.

[8]  R. Ahmed,et al.  Influenza Immunization in the Context of Preexisting Immunity. , 2020, Cold Spring Harbor perspectives in medicine.

[9]  L. Grohskopf,et al.  Prevention and Control of Seasonal Influenza with Vaccines: Recommendations of the Advisory Committee on Immunization Practices — United States, 2020–21 Influenza Season , 2020, MMWR. Recommendations and reports : Morbidity and mortality weekly report. Recommendations and reports.

[10]  C. Verschoor,et al.  Frailty Is Associated With Increased Hemagglutination-Inhibition Titers in a 4-Year Randomized Trial Comparing Standard- and High-Dose Influenza Vaccination , 2020, Open forum infectious diseases.

[11]  S. Klein,et al.  Commentary for the 'VSI: Aging and sex in immunity'. , 2020, Cellular immunology.

[12]  L. Rosella,et al.  The impact of repeated vaccination using 10-year vaccination history on protection against influenza in older adults: a test-negative design study across the 2010/11 to 2015/16 influenza seasons in Ontario, Canada , 2020, Euro surveillance : bulletin Europeen sur les maladies transmissibles = European communicable disease bulletin.

[13]  J. Nauta.  Adjusting for Imbalance in Pre-Vaccination State , 2020, Springer Series in Pharmaceutical Statistics.

[14]  T. Ross,et al.  Preexisting influenza specific immunity and vaccine effectiveness , 2019, Expert review of vaccines.

[15]  L. Brammer,et al.  The epidemiological signature of influenza B virus and its B/Victoria and B/Yamagata lineages in the 21st century , 2019, PloS one.

[16]  R. Kennedy,et al.  Immunosenescence: A systems-level overview of immune cell biology and strategies for improving vaccine responses , 2019, Experimental Gerontology.

[17]  Katelyn M. Gostic,et al.  Childhood immune imprinting to influenza A shapes birth year-specific risk during seasonal H1N1 and H3N2 epidemics , 2019, PLoS pathogens.

[18]  S. Klein,et al.  Age-associated changes in the impact of sex steroids on influenza vaccine responses in males and females , 2019, npj Vaccines.

[19]  P. Doherty,et al.  Recalling the Future: Immunological Memory Toward Unpredictable Influenza Viruses , 2019, Front. Immunol..

[20]  D. Matysiak-Klose,et al.  Estimating age-specific vaccine effectiveness using data from a large measles outbreak in Berlin, Germany, 2014/15: evidence for waning immunity , 2019, Euro surveillance : bulletin Europeen sur les maladies transmissibles = European communicable disease bulletin.

[21]  S. Leng,et al.  Chronic Low-grade Inflammatory Phenotype (CLIP) and Senescent Immune Dysregulation. , 2019, Clinical therapeutics.

[22]  G. Luscombe,et al.  Influenza infections in Australia 2009–2015: is there a combined effect of age and sex on susceptibility to virus subtypes? , 2019, BMC Infectious Diseases.

[23]  David L. Smith,et al.  Mortality, morbidity, and hospitalisations due to influenza lower respiratory tract infections, 2017: an analysis for the Global Burden of Disease Study 2017 , 2019, The Lancet Respiratory Medicine.

[24]  V. Narang,et al.  Influenza Vaccine-Induced Antibody Responses Are Not Impaired by Frailty in the Community-Dwelling Elderly With Natural Influenza Exposure , 2018, Front. Immunol..

[25]  A. Ellebedy.  Immunizing the Immune: Can We Overcome Influenza’s Most Formidable Challenge? , 2018, Vaccines.

[26]  M. Brytting,et al.  Impact of repeated influenza vaccinations in persons over 65 years of age: A large population-based cohort study of severe influenza over six consecutive seasons, 2011/12-2016/17. , 2018, Vaccine.

[27]  P. Wilson,et al.  Harnessing immune history to combat influenza viruses. , 2018, Current opinion in immunology.

[28]  M. Loeb,et al.  Does consecutive influenza vaccination reduce protection against influenza: A systematic review and meta-analysis. , 2018, Vaccine.

[29]  S. Klein,et al.  The Confluence of Sex Hormones and Aging on Immunity , 2018, Front. Immunol..

[30]  S. Trottier,et al.  Influenza vaccine effectiveness to prevent influenza-related hospitalizations and serious outcomes in Canadian adults over the 2011/12 through 2013/14 influenza seasons: A pooled analysis from the Canadian Immunization Research Network (CIRN) Serious Outcomes Surveillance (SOS Network). , 2018, Vaccine.

[31]  M. Bertolet,et al.  The effect of frailty on HAI response to influenza vaccine among community-dwelling adults ≥ 50 years of age , 2018, Human vaccines & immunotherapeutics.

[32]  B. Weinberger.  Vaccines for the elderly: current use and future challenges , 2018, Immunity & Ageing.

[33]  S. Pillet,et al.  The establishment of surrogates and correlates of protection: Useful tools for the licensure of effective influenza vaccines? , 2018, Human vaccines & immunotherapeutics.

[34]  P. Godoy,et al.  Repeated influenza vaccination for preventing severe and fatal influenza infection in older adults: a multicentre case–control study , 2018, Canadian Medical Association Journal.

[35]  P. Wilson,et al.  From Original Antigenic Sin to the Universal Influenza Virus Vaccine. , 2018, Trends in immunology.

[36]  A. Levêque,et al.  Effectiveness of influenza vaccines in preventing severe influenza illness among adults: A systematic review and meta-analysis of test-negative design case-control studies. , 2017, The Journal of infection.

[37]  James D. Allen,et al.  Impact of age and pre-existing influenza immune responses in humans receiving split inactivated influenza vaccine on the induction of the breadth of antibodies to influenza A strains , 2017, PloS one.

[38]  S. Klein,et al.  Sex and Gender Differences in the Outcomes of Vaccination over the Life Course. , 2017, Annual review of cell and developmental biology.

[39]  N. Bosco,et al.  Influenza vaccine response in community-dwelling German prefrail and frail individuals , 2017, Immunity & Ageing.

[40]  Edward A Belongia,et al.  Repeated annual influenza vaccination and vaccine effectiveness: review of evidence , 2017, Expert review of vaccines.

[41]  P. Kelly,et al.  Repeated Vaccination Does Not Appear to Impact Upon Influenza Vaccine Effectiveness Against Hospitalization With Confirmed Influenza , 2017, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[42]  S. Gravenstein,et al.  Vaccinations for the Older Adult. , 2016, Clinics in geriatric medicine.

[43]  Y. Poovorawan,et al.  The Success of a Universal Hepatitis B Immunization Program as Part of Thailand’s EPI after 22 Years’ Implementation , 2016, PloS one.

[44]  A. Díaz,et al.  Obesity decreases B cell responses in young and elderly individuals , 2016, Obesity.

[45]  C. Diazgranados,et al.  Correlates of Protection against Influenza in the Elderly: Results from an Influenza Vaccine Efficacy Trial , 2016, Clinical and Vaccine Immunology.

[46]  Aiping Wu,et al.  Antigenic Patterns and Evolution of the Human Influenza A (H1N1) Virus , 2015, Scientific Reports.

[47]  Kwok-Hung Chan,et al.  Age and Sex Differences in Rates of Influenza-Associated Hospitalizations in Hong Kong. , 2015, American journal of epidemiology.

[48]  Timothy B. Stockwell,et al.  The contrasting phylodynamics of human influenza B viruses , 2015, eLife.

[49]  T. Friedrich,et al.  Impact of Repeated Vaccination on Vaccine Effectiveness Against Influenza A(H3N2) and B During 8 Seasons , 2014, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[50]  C. Hannoun,et al.  The evolving history of influenza viruses and influenza vaccines , 2013, Expert review of vaccines.

[51]  Florian Krammer,et al.  Neutralizing Antibodies Against Previously Encountered Influenza Virus Strains Increase over Time: A Longitudinal Analysis , 2013, Science Translational Medicine.

[52]  J. Katz,et al.  Immunological assessment of influenza vaccines and immune correlates of protection , 2013, Expert review of vaccines.

[53]  M. Decker,et al.  Safety and immunogenicity of a quadrivalent inactivated influenza vaccine compared to licensed trivalent inactivated influenza vaccines in adults. , 2013, Vaccine.

[54]  R. Newson.  Sensible Parameters for Univariate and Multivariate Splines , 2012 .

[55]  L. Fried,et al.  Frailty is associated with impairment of vaccine-induced antibody response and increase in post-vaccination influenza infection in community-dwelling older adults. , 2011, Vaccine.

[56]  Andrew Pekosz,et al.  The Xs and Y of immune responses to viral vaccines. , 2010, The Lancet. Infectious diseases.

[57]  Raul Rabadan,et al.  Differences in Patient Age Distribution between Influenza A Subtypes , 2009, PloS one.

[58]  A. Falsey,et al.  Randomized, double-blind controlled phase 3 trial comparing the immunogenicity of high-dose and standard-dose influenza vaccine in adults 65 years of age and older. , 2009, The Journal of infectious diseases.

[59]  D. Weiskopf,et al.  Biology of immune responses to vaccines in elderly persons. , 2008, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[60]  R. Jennings,et al.  Interpretation of responses and protective levels of antibody against attenuated influenza A viruses using single radial haemolysis , 1984, Journal of Hygiene.

[61]  A. S. Beare,et al.  The role of serum haemagglutination-inhibiting antibody in protection against challenge infection with influenza A2 and B viruses , 1972, Epidemiology and Infection.