Age-Dependent Neutralization of SARS-CoV-2 and P.1 Variant by Vaccine Immune Serum Samples | Vaccination | JAMA | JAMA Network
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Figure 1.  SARS-CoV-2–Specific Antibody Levels
SARS-CoV-2–Specific Antibody Levels

Enzyme-linked immunosorbent assay measurement of SARS-CoV-2 spike receptor-binding domain-specific antibody levels and association with age at time of vaccination for 50 participants 14 days after receiving their second vaccine dose. Prevaccination samples for all participants were below the limit of detection, indicating no prior exposure. Postvaccination samples displayed a significant negative association with age. The dotted line indicates the lower limit of quantification.

Figure 2.  Neutralization of Live SARS-CoV-2 Clinical Isolates
Neutralization of Live SARS-CoV-2 Clinical Isolates

Live virus neutralization of participant serum samples collected 14 days after the second vaccine dose. Neutralization experiments were performed with the USA-WA1/2020 strain and P.1 variant. Both show a significant negative association with participant age. The dotted line indicates the lower limit of quantification.

1.
Polack  FP, Thomas  SJ, Kitchin  N,  et al; C4591001 Clinical Trial Group.  Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine.   N Engl J Med. 2020;383(27):2603-2615. doi:10.1056/NEJMoa2034577PubMedGoogle ScholarCrossref
2.
Kontopantelis  E, Mamas  MA, Deanfield  J, Asaria  M, Doran  T.  Excess mortality in England and Wales during the first wave of the COVID-19 pandemic.   J Epidemiol Community Health. 2021;75(3):213-223.PubMedGoogle Scholar
3.
Haas  EJ, Angulo  FJ, McLaughlin  JM,  et al.  Impact and effectiveness of mRNA BNT162b2 vaccine against SARS-CoV-2 infections and COVID-19 cases, hospitalisations, and deaths following a nationwide vaccination campaign in Israel: an observational study using national surveillance data.   Lancet. 2021;397(10287):1819-1829. doi:10.1016/S0140-6736(21)00947-8PubMedGoogle ScholarCrossref
4.
Baden  LR, El Sahly  HM, Essink  B,  et al; COVE Study Group.  Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine.   N Engl J Med. 2021;384(5):403-416 doi:10.1056/NEJMoa2035389PubMedGoogle ScholarCrossref
5.
Khoury  DS, Cromer  D, Reynaldi  A,  et al.  Neutralizing antibody levels are highly predictive of immune protection from symptomatic SARS-CoV-2 infection.   Nat Med. Published online May 17, 2021. doi:10.1038/s41591-021-01377-8PubMedGoogle Scholar
6.
 COVID-19 vaccine breakthrough infections reported to CDC—United States, January 1-April 30, 2021.   MMWR Morb Mortal Wkly Rep. 2021;70(21);792–793. doi:10.15585/mmwr.mm7021e3PubMedGoogle ScholarCrossref
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    Effect of COVID-19 vaccine on SARS-CoV-2 variants in age subpopulation
    takuma hayashi, MBBS, DMSci, GMRC, PhD. | National Hospital Organization Kyoto Medical Center
    In the clinical study conducted by Bates et al., initial vaccine-elicited neutralizing antibody titers against SARS-CoV-2 were negatively associated with age, resulting in a diminished ability to neutralize SARS-CoV-2 in vitro. Neutralizing titers against gamma type SARS-CoV-2 variants were reduced across all ages, although the magnitude of the age-dependent difference was smaller.

    Due to its strong infectivity, delta type SARS-CoV-2 variant has been shown to spread worldwide. The immune effect of COVID-19 mRNA vaccine (BNT162b2) vaccination against delta type SARS-CoV-2 variants has not been clearly understood. The immune effect of COVID-19 mRNA vaccine (BNT162b2) vaccination against delta type SARS-CoV-2
    variants in each subpopulation defined by age and/or gender must be investigated.

    Neutralizing antibody titers against SARS-CoV-2 are thought to be strongly correlated with protection from SARS-CoV-2 infection; however, the threshold of this protection induced by COVID-19 mRNA vaccine (BNT162b2) has not yet been precisely determined. Future studies should specifically address whether the reduced antibody levels seen among older vaccinated individuals lead to concomitantly diminished protection.

    Dr. Hayashi T. and Dr. Konishi I.
    National Hospital Organization Kyoto Medical Center
     
    CONFLICT OF INTEREST: None Reported
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    Research Letter
    July 21, 2021

    Age-Dependent Neutralization of SARS-CoV-2 and P.1 Variant by Vaccine Immune Serum Samples

    Author Affiliations
    • 1Department of Molecular Microbiology & Immunology, Oregon Health & Science University, Portland
    • 2Medical Scientist Training Program, Oregon Health & Science University, Portland
    • 3Division of Infectious Diseases, Oregon Health & Science University, Portland
    JAMA. Published online July 21, 2021. doi:10.1001/jama.2021.11656

    Vaccination with 2 doses of the BNT162b2 vaccine (Pfizer-BioNTech) reportedly provides 95% protection from COVID-19.1 However, patient age is known to contribute to the risk of COVID-19 incidence and severity.2 We examined the relationship between age and neutralizing antibody titers against the early SARS-CoV-2 USA-WA1/2020 strain and the P.1 variant of concern after 2 doses of the BNT162b2 vaccine.

    Methods

    The Oregon Health & Science University conducted large-scale vaccination of all workforce members in accordance with Oregon vaccination guidelines between December 2020 and February 2021. Individuals were enrolled in this study during their first vaccination visit and serum samples were collected prior to receipt of the first dose and 14 days after receipt of the second dose of the BNT162b2 vaccine. Study participants were selected randomly from a larger vaccine study cohort to maintain equal sex and age distribution.

    SARS-CoV-2 spike receptor-binding domain-specific antibody levels were measured by enzyme-linked immunosorbent assays, and 50% effective titers (EC50) were calculated. SARS-CoV-2 50% neutralizing titers were determined by focus reduction neutralization tests (FRNT50) using live clinical isolates of the original SARS-CoV-2 strain (USA-WA1/2020) and the P.1 variant. Associations between age and EC50 and FRNT50 were determined by fitting a linear model to log-transformed data in Graphpad Prism, version 9.0.2. Two-tailed P values were calculated by F test with a zero-slope null hypothesis and a significance cutoff of P .05.

    This study was performed in accordance with the institutional review board at Oregon Health & Science University. Written informed consent was obtained from participants. Additional method details of the serum collection and laboratory analyses can be found in the eAppendix in the Supplement.

    Results

    A total of 50 individuals were enrolled in this study (27 [54%] women; median [range] age, 50.5 [21-82] years); prevaccination EC50 measurements were below the limit of quantification for all participants, indicating no prior exposures. Postvaccination EC50 measurements showed a significant negative association with age (R2 = 0.19; P = .002) (Figure 1).

    Robust neutralizing responses were observed in all participants against the original strain (USA-WA1/2020), with a geometric mean titer (GMT) serum dilution of 393 (95% CI, 302-510). Responses were lower against the P.1 variant, with a GMT of 91 (95% CI, 71-116), representing a 76.8% reduction. For both USA-WA1/2020 and P.1, age was significantly negatively correlated with FRNT50 (P < .001 and P = .001) (Figure 2). For the USA-WA1/2020 strain, the youngest participants (20-29 years; n = 8) had a GMT of 938 (95% CI, 608-1447) and the oldest participants (70-82 years; n = 9) had a GMT of 138 (95% CI, 74-257), representing an 85% reduction (P < .001). For the P.1 variant, the youngest participants had a GMT of 165 (95% CI, 78-349) and the oldest participants had a GMT of 66 (95% CI, 51-86), representing a 60% reduction (P = .03).

    Discussion

    In this study, initial vaccine-elicited neutralizing antibody titers were negatively associated with age, resulting in a diminished ability to neutralize SARS-CoV-2 in vitro. Neutralizing titers against P.1 were reduced across all ages, although the magnitude of the age-dependent difference was smaller. Interim clinical trial data did not identify age as a contributing factor to overall vaccine efficacy.1 However, recent studies in vaccinated populations have found a measurable increase in COVID-19 cases among vaccinated older adults.3,4 The data from the current study are consistent with neutralizing antibody levels playing an important role in this observation.

    Neutralizing antibody titers are thought to be strongly correlated with protection from infection; however, the threshold of this protection has not yet been precisely determined.5 Future studies should specifically address whether the reduced antibody levels seen among older vaccinated individuals lead to concomitantly diminished protection. Additionally, the emerging SARS-CoV-2 variants of concern, including P.1, B.1.1.7, and B.1.351, have been widely reported to be less well-neutralized by vaccine-induced antibodies and are responsible for a majority of breakthrough infections, according to a May 2021 report.6 The compounding effects of reduced neutralizing antibody titers due to both age and the variants of concern should be considered when designing policies around booster vaccinations. Limitations of this study include the small sample size and the possibility of unrecognized infection prior to vaccination.

    Section Editor: Jody W. Zylke, MD, Deputy Editor.
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    Article Information

    Corresponding Author: Fikadu G. Tafesse, PhD, Department of Molecular Microbiology & Immunology, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239 (tafesse@ohsu.edu).

    Accepted for Publication: June 29, 2021.

    Published Online: July 21, 2021. doi:10.1001/jama.2021.11656

    Author Contributions: Dr Tafesse had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Mr Bates and Mr Leier contributed equally to this work.

    Concept and design: Bates, Leier, Lyski, Curlin, Messer, Tafesse.

    Acquisition, analysis, or interpretation of data: All authors.

    Drafting of the manuscript: Bates, Leier.

    Critical revision of the manuscript for important intellectual content: All authors.

    Statistical analysis: Bates, Messer.

    Obtained funding: Curlin, Messer, Tafesse.

    Administrative, technical, or material support: Bates, Lyski, Goodman, Curlin, Tafesse.

    Supervision: Curlin, Messer, Tafesse.

    Conflict of Interest Disclosures: Dr Curlin reported receiving grants from the M.J. Murdock Charitable Trust and the Oregon Health & Science University Foundation for unrestricted COVID-19 research during the conduct of the study. Dr Tafesse reported receiving grants from Oregon Health & Science University Biomedical Innovation Program during the conduct of the study. No other disclosures were reported.

    Funding/Support: This study was funded in part by an unrestricted grant from the M.J. Murdock Charitable Trust, by National Institutes of Health training grant T32AI747225 on Interactions at the Microbe-Host Interface, Oregon Health & Science University Innovative IDEA grant 1018784, and National Institutes of Health grant R01AI145835.

    Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

    Additional Contributions: We would like to acknowledge the efforts of the Oregon Health & Science University COVID-19 serology research team for their assistance with sample acquisition, data collection, and statistical analysis, including Christopher Malibiran, BS; Cynthia Martinez, BS; David Xthona Lee, BA; Devin Schoen, BS; Felicity Coulter, MS; Haley Miller, BS; Hiro Ross, BS; Joseph Easly, BS; Kristin Bialobok, MSN; Laura Craft, BS; Madison Egan, BS-RD; Madison Wahl, BA; Marcus Curlin; Mari Tasche, BS; Matthew Strnad, BS; Maya Herzig, BS; Olivia Glatt, BA; Peter Sullivan, BA; Rick Mathews, BE; Sara McCrimmon, MPH; Sarah Siegel, PhD; Taylor Anderson, MD; Teresa Xu, BA; and Zhengchun Lu, MBBS-PhD. We also thank Savannah McBride, BA (Department of Molecular Microbiology & Immunology, Oregon Health & Science University), for technical help and Endale Tafesse, PhD (Department of Plant Sciences, University of Saskatchewan), for his advice on data analysis. None of these individuals were compensated for their contributions. We are deeply grateful for the Oregon Health & Science University faculty, staff, and patients who contributed to this study.

    References
    1.
    Polack  FP, Thomas  SJ, Kitchin  N,  et al; C4591001 Clinical Trial Group.  Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine.   N Engl J Med. 2020;383(27):2603-2615. doi:10.1056/NEJMoa2034577PubMedGoogle ScholarCrossref
    2.
    Kontopantelis  E, Mamas  MA, Deanfield  J, Asaria  M, Doran  T.  Excess mortality in England and Wales during the first wave of the COVID-19 pandemic.   J Epidemiol Community Health. 2021;75(3):213-223.PubMedGoogle Scholar
    3.
    Haas  EJ, Angulo  FJ, McLaughlin  JM,  et al.  Impact and effectiveness of mRNA BNT162b2 vaccine against SARS-CoV-2 infections and COVID-19 cases, hospitalisations, and deaths following a nationwide vaccination campaign in Israel: an observational study using national surveillance data.   Lancet. 2021;397(10287):1819-1829. doi:10.1016/S0140-6736(21)00947-8PubMedGoogle ScholarCrossref
    4.
    Baden  LR, El Sahly  HM, Essink  B,  et al; COVE Study Group.  Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine.   N Engl J Med. 2021;384(5):403-416 doi:10.1056/NEJMoa2035389PubMedGoogle ScholarCrossref
    5.
    Khoury  DS, Cromer  D, Reynaldi  A,  et al.  Neutralizing antibody levels are highly predictive of immune protection from symptomatic SARS-CoV-2 infection.   Nat Med. Published online May 17, 2021. doi:10.1038/s41591-021-01377-8PubMedGoogle Scholar
    6.
     COVID-19 vaccine breakthrough infections reported to CDC—United States, January 1-April 30, 2021.   MMWR Morb Mortal Wkly Rep. 2021;70(21);792–793. doi:10.15585/mmwr.mm7021e3PubMedGoogle ScholarCrossref
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