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

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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