Effects of age, sex, serostatus, and underlying comorbidities on humoral response post-SARS-CoV-2 Pfizer-BioNTech mRNA vaccination: a systematic review

Abstract With the advent of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic, several vaccines have been developed to mitigate its spread and prevent adverse consequences of the Coronavirus Disease 2019 (COVID-19). The mRNA technology is an unprecedented vaccine, usually given in two doses to prevent SARS-CoV-2 infections. Despite effectiveness and safety, inter-individual immune response heterogeneity has been observed in recipients of mRNA-based vaccines. As a novel disease, the specific immune response mechanism responsible for warding off COVID-19 remains unclear at this point. However, significant evidence suggests that humoral response plays a crucial role in affording immunoprotection and preventing debilitating sequelae from COVID-19. As such, this paper focused on the possible effects of age, sex, serostatus, and comorbidities on humoral response (i.e. total antibodies, IgG, and/or IgA) of different populations post-mRNA-based Pfizer-BioNTech vaccination. A systematic search of literature was performed through PubMed, Cochrane CENTRAL, Google Scholar, Science Direct, medRxiv, and Research Square. Studies were included if they reported humoral response to COVID-19 mRNA vaccines. A total of 32 studies were identified and reviewed, and the percent differences of means of reported antibody levels were calculated for comparison. Findings revealed that older individuals, male sex, seronegativity, and those with more comorbidities mounted less humoral immune response. Given these findings, several recommendations were proposed regarding the current vaccination practices. These include giving additional doses of vaccination for immunocompromised and elderly populations. Another recommendation is conducting clinical trials in giving a combined scheme of mRNA vaccines, protein vaccines, and vector-based vaccines.

[1]  S. Omer,et al.  SARS-CoV-2 Vaccine Effectiveness in a High-Risk National Population in a Real-World Setting , 2021, Annals of Internal Medicine.

[2]  Guilhem Cavaillé,et al.  Efficacy of the BNT162b2 mRNA COVID-19 vaccine in a haemodialysis cohort. , 2021, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[3]  P. Dormitzer,et al.  Safety, Immunogenicity, and Efficacy of the BNT162b2 Covid-19 Vaccine in Adolescents , 2021, The New England journal of medicine.

[4]  R. Müller,et al.  Application of subject-specific adaptive mechanical loading for bone healing in a mouse tail vertebral defect , 2020, Scientific Reports.

[5]  Y. Yuzawa,et al.  Aspects of immune dysfunction in end-stage renal disease. , 2008, Clinical journal of the American Society of Nephrology : CJASN.

[6]  S. Kelsen,et al.  Heightened COVID-19 Vaccine Response following SARS-CoV-2 Infection , 2021, medRxiv.

[7]  Wilbur H. Chen,et al.  Understanding immunosenescence and its impact on vaccination of older adults. , 2020, Vaccine.

[8]  D. Hricik,et al.  Effects of Influenza Immunization on Humoral and Cellular Alloreactivity in Humans , 2010, Transplantation.

[9]  E. Dolgin How COVID unlocked the power of RNA vaccines , 2021, Nature.

[10]  G. Ciliberto,et al.  Fifth-week immunogenicity and safety of anti-SARS-CoV-2 BNT162b2 vaccine in patients with multiple myeloma and myeloproliferative malignancies on active treatment: preliminary data from a single institution , 2021, Journal of Hematology & Oncology.

[11]  J. Dogné,et al.  Early antibody response in health-care professionals after two doses of SARS-CoV-2 mRNA vaccine (BNT162b2) , 2021, Clinical Microbiology and Infection.

[12]  Cameron R. Wolfe,et al.  COVID-19 vaccination in our transplant recipients: The time is now , 2021, The Journal of Heart and Lung Transplantation.

[13]  Very low intensity ultrasounds as a new strategy to improve selective delivery of nanoparticles-complexes in cancer cells , 2019, Journal of experimental & clinical cancer research : CR.

[14]  M. Giordano,et al.  Immune system and COVID-19 by sex differences and age , 2021, Women's health.

[15]  K. Greenlund,et al.  Estimated County-Level Prevalence of Selected Underlying Medical Conditions Associated with Increased Risk for Severe COVID-19 Illness — United States, 2018 , 2020, MMWR. Morbidity and mortality weekly report.

[16]  J. Villard,et al.  De Novo Anti‐HLA Antibody After Pandemic H1N1 and Seasonal Influenza Immunization in Kidney Transplant Recipients , 2011, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[17]  V. Caudwell,et al.  SARS-CoV-2 Antibody Response After a Third Dose of the BNT162b2 Vaccine in Patients Receiving Maintenance Hemodialysis or Peritoneal Dialysis , 2021, American Journal of Kidney Diseases.

[18]  L. Gunaratnam,et al.  Short-term antibody response after 1 dose of BNT162b2 vaccine in patients receiving hemodialysis , 2021, Canadian Medical Association Journal.

[19]  I. Hozo,et al.  Estimating the mean and variance from the median, range, and the size of a sample , 2005, BMC medical research methodology.

[20]  M. Vidali,et al.  Evaluation of Anti-SARS-Cov-2 S-RBD IgG Antibodies after COVID-19 mRNA BNT162b2 Vaccine , 2021, Diagnostics.

[21]  G. Shefer,et al.  Efficacy of the BNT162b2 mRNA COVID-19 vaccine in patients with chronic lymphocytic leukemia , 2021, Blood.

[22]  J. Vencovský,et al.  Plasma Hsp90 levels in patients with systemic sclerosis and relation to lung and skin involvement: a cross-sectional and longitudinal study , 2021, Scientific Reports.

[23]  A. Oberg,et al.  The Impact of Immunosenescence on Humoral Immune Response Variation after Influenza A/H1N1 Vaccination in Older Subjects , 2015, PloS one.

[24]  M. Edelstein,et al.  Impact of age, ethnicity, sex and prior infection status on immunogenicity following a single dose of the BNT162b2 mRNA COVID-19 vaccine: real-world evidence from healthcare workers, Israel, December 2020 to January 2021 , 2021, Euro surveillance : bulletin Europeen sur les maladies transmissibles = European communicable disease bulletin.

[25]  M. Spitzer,et al.  Systemic immunity in cancer , 2021, Nature Reviews Cancer.

[26]  Nguyen H. Tran,et al.  Reactogenicity and immunogenicity after a late second dose or a third dose of ChAdOx1 nCoV-19 in the UK: a substudy of two randomised controlled trials (COV001 and COV002) , 2021, The Lancet.

[27]  H. Heppner,et al.  Comorbidities in the Elderly and Their Possible Influence on Vaccine Response. , 2020, Interdisciplinary topics in gerontology and geriatrics.

[28]  Ezekiel J Emanuel,et al.  Fair Allocation of Scarce Medical Resources in the Time of Covid-19. , 2020, The New England journal of medicine.

[29]  P. M. Albano Cross-contamination in Molecular Diagnostic Laboratories in Low- and Middle-income Countries: A Challenge to COVID-19 Testing , 2020, Philippine Journal of Pathology.

[30]  G. Tedeschi,et al.  Preliminary evidence of blunted humoral response to SARS-CoV-2 mRNA vaccine in multiple sclerosis patients treated with ocrelizumab , 2021, Neurological Sciences.

[31]  F. Abboud,et al.  The immune system and hypertension , 2014, Immunologic Research.

[32]  S. Adamopoulos,et al.  Immunogenicity of SARS-CoV-2 BNT162b2 vaccine in solid organ transplant recipients , 2021, American Journal of Transplantation.

[33]  M. Plebani,et al.  Antibody response to first and second dose of BNT162b2 in a cohort of characterized healthcare workers , 2021, Clinica Chimica Acta.

[34]  A. Kribben,et al.  Humoral Response to SARS-CoV-2-Vaccination with BNT162b2 (Pfizer-BioNTech) in Patients on Hemodialysis , 2021, Vaccines.

[35]  M. Hudgens,et al.  Obesity is associated with impaired immune response to influenza vaccination in humans , 2011, International Journal of Obesity.

[36]  G. Rimmelzwaan,et al.  Response to influenza virus vaccination during chemotherapy in patients with breast cancer. , 2011, Annals of oncology : official journal of the European Society for Medical Oncology.

[37]  G. Lippi,et al.  COVID-19: unravelling the clinical progression of nature’s virtually perfect biological weapon , 2020, Annals of translational medicine.

[38]  D. Delgado,et al.  Impact of Adjuvanted H1N1 Vaccine on Cell‐Mediated Rejection in Heart Transplant Recipients , 2011, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[39]  Qiming Wang,et al.  MEK inhibitors for the treatment of non-small cell lung cancer , 2021, Journal of Hematology & Oncology.

[40]  P. Thompson,et al.  Inhibiting PAD2 enhances the anti-tumor effect of docetaxel in tamoxifen-resistant breast cancer cells , 2019, Journal of Experimental & Clinical Cancer Research.

[41]  D. Montefiori,et al.  Safety and immunogenicity of SARS-CoV-2 variant mRNA vaccine boosters in healthy adults: an interim analysis , 2021, Nature Medicine.

[42]  A. Reiner-Benaim,et al.  Serologic Status and Toxic Effects of the SARS-CoV-2 BNT162b2 Vaccine in Patients Undergoing Treatment for Cancer , 2021, Annals of Oncology.

[43]  Feifei Qiu,et al.  Impacts of cigarette smoking on immune responsiveness: Up and down or upside down? , 2016, Oncotarget.

[44]  V. Simon,et al.  Robust spike antibody responses and increased reactogenicity in seropositive individuals after a single dose of SARS-CoV-2 mRNA vaccine , 2021, medRxiv.

[45]  J. V. Van Eyk,et al.  Antibody responses to the BNT162b2 mRNA vaccine in individuals previously infected with SARS-CoV-2 , 2021, Nature Medicine.

[46]  N. Moskovits,et al.  Evaluation of Seropositivity Following BNT162b2 Messenger RNA Vaccination for SARS-CoV-2 in Patients Undergoing Treatment for Cancer , 2021, JAMA oncology.

[47]  G. Alter,et al.  Sex differences in vaccine-induced humoral immunity , 2018, Seminars in Immunopathology.

[48]  M. Ison,et al.  Influenza Vaccination in the Organ Transplant Recipient: Review and Summary Recommendations † , 2011, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[49]  P. Hoff,et al.  Immunogenicity and safety of anti-SARS-CoV-2 mRNA vaccines in patients with chronic inflammatory conditions and immunosuppressive therapy in a monocentric cohort , 2021, Annals of the Rheumatic Diseases.

[50]  E. Verdin,et al.  SARS-CoV-2, COVID-19 and the aging immune system , 2021, Nature Aging.

[51]  P. Tyack,et al.  Modeling Tissue and Blood Gas Kinetics in Coastal and Offshore Common Bottlenose Dolphins, Tursiops truncatus , 2018, Front. Physiol..

[52]  C. Farina,et al.  Antibody response to SARS‐CoV‐2 vaccination is extremely vivacious in subjects with previous SARS‐CoV‐2 infection , 2021, medRxiv.

[53]  D. Segev,et al.  Safety and Immunogenicity of a Third Dose of SARS-CoV-2 Vaccine in Solid Organ Transplant Recipients: A Case Series , 2021, Annals of Internal Medicine.

[54]  Zhongwei Zhang,et al.  Anti‐SARS‐CoV‐2 IgG levels in relation to disease severity of COVID‐19 , 2021, Journal of medical virology.

[55]  S. Knight,et al.  Does vaccination in solid-organ transplant recipients result in adverse immunologic sequelae? A systematic review and meta-analysis. , 2018, The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation.

[56]  Yaokai Chen,et al.  Patterns of IgG and IgM antibody response in COVID-19 patients , 2020, Emerging microbes & infections.

[57]  Quentin J. Leclerc,et al.  The impact of local and national restrictions in response to COVID-19 on social contacts in England: a longitudinal natural experiment , 2021, BMC Medicine.

[58]  M. Kramer,et al.  Early humoral response among lung transplant recipients vaccinated with BNT162b2 vaccine , 2021, The Lancet Respiratory Medicine.

[59]  A. Lerner,et al.  The World Incidence and Prevalence of Autoimmune Diseases is Increasing , 2015 .

[60]  M. Fernández,et al.  Impact of Obesity and Metabolic Syndrome on Immunity. , 2016, Advances in nutrition.

[61]  B. Eley Faculty Opinions recommendation of Safety, Immunogenicity, and Efficacy of the BNT162b2 Covid-19 Vaccine in Adolescents. , 2021, Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature.

[62]  G. Lippi,et al.  Anti-SARS-CoV-2 Receptor-Binding Domain Total Antibodies Response in Seropositive and Seronegative Healthcare Workers Undergoing COVID-19 mRNA BNT162b2 Vaccination , 2021, Diagnostics.

[63]  J. Lord The effect of aging of the immune system on vaccination responses , 2013, Human vaccines & immunotherapeutics.

[64]  Å. Lundkvist,et al.  Evaluation of a COVID-19 IgM and IgG rapid test; an efficient tool for assessment of past exposure to SARS-CoV-2 , 2020, Infection ecology & epidemiology.

[65]  H. Itoh,et al.  Hypertension as a Metabolic Disorder and the Novel Role of the Gut , 2019, Current Hypertension Reports.

[66]  S. Klein,et al.  Sex differences in immune responses , 2016, Nature Reviews Immunology.

[67]  M. Veldhoen,et al.  Humoral Immune Response of SARS‐CoV‐2–Infected Patients with Cancer: Influencing Factors and Mechanisms , 2021, The oncologist.

[68]  K. Dooley,et al.  Tuberculosis and diabetes mellitus: convergence of two epidemics. , 2009, The Lancet. Infectious diseases.

[69]  G. Lippi,et al.  Characterization of the significant decline in humoral immune response six months post‐SARS‐CoV‐2 mRNA vaccination: A systematic review , 2021, medRxiv.

[70]  G. Piccoli,et al.  Neutralizing SARS-CoV-2 antibody response in dialysis patients after the first dose of the BNT162b2 mRNA COVID-19 vaccine: the war is far from being won , 2021, Kidney International.

[71]  G. Shefer,et al.  Immunogenicity and safety of the BNT162b2 mRNA COVID-19 vaccine in adult patients with autoimmune inflammatory rheumatic diseases and in the general population: a multicentre study , 2021, Annals of the Rheumatic Diseases.

[72]  E. Walsh,et al.  SARS-CoV-2 Neutralization with BNT162b2 Vaccine Dose 3 , 2021, The New England journal of medicine.

[73]  Shao-bo Shi,et al.  Analysis of 92 deceased patients with COVID‐19 , 2020, Journal of medical virology.

[74]  L. Rénia,et al.  COVID-19 vaccines and kidney disease , 2021, Nature Reviews Nephrology.

[75]  M. González-Gay,et al.  Obesity, Fat Mass and Immune System: Role for Leptin , 2018, Front. Physiol..

[76]  L. Tserel,et al.  Antibody response after COVID-19 mRNA vaccination in relation to age, sex, and side effects , 2021, medRxiv.

[77]  Fu-Sheng Wang,et al.  Human autoimmune diseases: a comprehensive update , 2015, Journal of internal medicine.

[78]  E. Grundberg,et al.  Humoral immune responses during SARS-CoV-2 mRNA vaccine administration in seropositive and seronegative individuals , 2021, BMC Medicine.

[79]  A. Kribben,et al.  Impaired Humoral Response in Renal Transplant Recipients to SARS-CoV-2 Vaccination with BNT162b2 (Pfizer-BioNTech) , 2021, Viruses.

[80]  Valentina Perri,et al.  Increased sCD163 and sCD14 Plasmatic Levels and Depletion of Peripheral Blood Pro-Inflammatory Monocytes, Myeloid and Plasmacytoid Dendritic Cells in Patients With Severe COVID-19 Pneumonia , 2021, Frontiers in Immunology.

[81]  G. Lippi,et al.  Optimizing effectiveness of COVID-19 vaccination: will laboratory stewardship play a role? , 2021, Clinical chemistry and laboratory medicine.

[82]  Jonathan C. Brown,et al.  Effect of previous SARS-CoV-2 infection on humoral and T-cell responses to single-dose BNT162b2 vaccine , 2021, The Lancet.

[83]  J. Achard,et al.  Humoral Response after SARS-CoV-2 mRNA Vaccination in a Cohort of Hemodialysis Patients and Kidney Transplant Recipients , 2021, Journal of the American Society of Nephrology : JASN.

[84]  G. Lepperdinger,et al.  How sex and age affect immune responses, susceptibility to infections, and response to vaccination , 2015, Aging cell.

[85]  Zena Werb,et al.  Roles of the immune system in cancer: from tumor initiation to metastatic progression , 2018, Genes & development.

[86]  R. Trimble COVID-19 Dashboard , 2020 .

[87]  B. Mustanski,et al.  Comparison of IgG and neutralizing antibody responses after one or two doses of COVID-19 mRNA vaccine in previously infected and uninfected persons , 2021, medRxiv.

[88]  C. Mai,et al.  Therapeutic challenges and current immunomodulatory strategies in targeting the immunosuppressive pancreatic tumor microenvironment , 2019, Journal of Experimental & Clinical Cancer Research.

[89]  A. Lenzi,et al.  Central obesity, smoking habit, and hypertension are associated with lower antibody titres in response to COVID‐19 mRNA vaccine , 2021, Diabetes/metabolism research and reviews.

[90]  H. Ulmer,et al.  The Safety and Immunogenicity of the mRNA-BNT162b2 SARS-CoV-2 Vaccine in Hemodialysis Patients , 2021, Frontiers in Immunology.

[91]  Guilhem Cavaillé,et al.  Efficacy of the BNT162b2 mRNA Covid-19 Vaccine in a hemodialysis cohort , 2021, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[92]  H. Schaal,et al.  Age-dependent immune response to the Biontech/Pfizer BNT162b2 COVID-19 vaccination , 2021, medRxiv.

[93]  J. Snowdon,et al.  Emergence of Drift Variants That May Affect COVID-19 Vaccine Development and Antibody Treatment , 2020, Pathogens.

[94]  Yan-feng Wang,et al.  The effect of estrogen in coronavirus disease 2019 , 2021, American journal of physiology. Lung cellular and molecular physiology.

[95]  D. Schwartz,et al.  Reduced humoral response to mRNA SARS-CoV-2 BNT162b2 vaccine in kidney transplant recipients without prior exposure to the virus , 2021, American Journal of Transplantation.

[96]  E. Angelakis,et al.  Impact of Age and Sex on Antibody Response Following the Second Dose of COVID-19 BNT162b2 mRNA Vaccine in Greek Healthcare Workers , 2021, Microorganisms.

[97]  N. Uriel,et al.  COVID-19 in solid organ transplant recipients: Initial report from the US epicenter , 2020, American Journal of Transplantation.

[98]  O. Levtzion-korach,et al.  Safety and humoral responses to BNT162b2 mRNA vaccination of SARS-CoV-2 previously infected and naive populations , 2021, Scientific Reports.

[99]  F. Gobba,et al.  Neutralizing Anti-SARS-CoV-2 Antibody Titer and Reported Adverse Effects, in a Sample of Italian Nursing Home Personnel after Two Doses of the BNT162b2 Vaccine Administered Four Weeks Apart , 2021, Vaccines.

[100]  S. Merler,et al.  The risk of symptomatic infection during a second COVID-19 wave, in SARS-CoV-2 seropositive individuals. , 2021, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[101]  V. Lauschke,et al.  Immunogenicity of the BNT162b2 vaccine in frail or disabled nursing home residents: COVID‐A study , 2021, Journal of the American Geriatrics Society.

[102]  G. Ciliberto,et al.  Initial observations on age, gender, BMI and hypertension in antibody responses to SARS-CoV-2 BNT162b2 vaccine , 2021, EClinicalMedicine.

[103]  I. Drexler,et al.  Adjusted booster schedules disperse age-dependent differences in antibody titers benefitting risk populations - Update to: Age-dependent Immune Response to the BioNTech/Pfizer BNT162b2 Coronavirus Disease 2019 Vaccination , 2022, medRxiv.

[104]  D. Gudbjartsson,et al.  Age and Influenza-Specific Pre-Vaccination Antibodies Strongly Affect Influenza Vaccine Responses in the Icelandic Population whereas Disease and Medication Have Small Effects , 2018, Front. Immunol..