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Waning Immune Humoral Response to BNT162b2 Covid-19 Vaccine over 6 Months

Our take —

Data on the durability of protection offered by SARS-CoV-2 vaccines has been limited. This study demonstrated a significant decline in the humoral (antibody) response in the six months following administration of the second dose of the BNT162b2 vaccine (Pfizer BioNTech). This reduction was more pronounced among men, older participants, and those who were immune suppressed. Despite waning antibody levels, breakthrough infection was identified in only 25 (0.5%) study participants, demonstrating that vaccines remain highly effective. The host immune response to viral infection is incredibly complex, and antibodies are only one component of this response. In addition, the minimum antibody levels required to prevent infection have not yet been established, making it difficult to contextualize the data presented here. However, a cautious interpretation supports the use of an additional vaccine dose to boost humoral responses in high-risk individuals, including the elderly and those with immunosuppression.

Study design

Prospective Cohort

Study population and setting

Global vaccination against SARS-CoV-2 continues to progress at a rapid pace, but few data have been reported on the durability of protection. This prospective study assessed the dynamics of the humoral (antibody-based) immune response to SARS-CoV-2 in the six months following receipt of the second dose of the BNT162b2 vaccine (Pfizer BioNTech), using samples collected from Israeli healthcare workers (n= 4,868) between December 2020 and July 2021. All participants were seronegative at study enrollment, prior to receipt of the first vaccine dose. Anti-spike IgG antibody levels and neutralizing antibody titers were measured prior to vaccine receipt and monthly for six months. PCR testing and anti-N (nucleocapsid) IgG antibody screening was used to rule out breakthrough SARS-CoV-2 infection among symptomatic participants and/or those with substantial increases in antibody titers between visits. Demographic data was collected for study participants using a computer-based survey. Linear mixed models were used to examine the kinetics of the antibody response to vaccination and to identify factors associated with lower antibody levels six months after vaccine receipt.

Summary of Main Findings

The highest antibody responses were observed in the first thirty days post vaccination. These levels consistently decreased by a factor of 18.3 over the next six months. Titers of neutralizing antibody also decreased rapidly for the first three months (factor of 3.9), but this decay slowed between months three and six (factor of 1.2). IgG antibody levels and neutralizing antibody titers were highly correlated, but this relationship was dependent on the time since vaccine administration. At the end of the study period, neutralizing antibody titers were significantly lower among men, participants older than 65 years, and those with a history of immunosuppression. During the study period, 20/4,868 (0.4%) participants were diagnosed with breakthrough SARS-CoV-2 infection via PCR testing, and 5 participants developed anti-N antibody reactivity, also indicating vaccine breakthrough.

Study Strengths

This study represents the first large-scale effort to assess the durability of the humoral immune response to SARS-CoV-2 following full vaccination with the Pfizer BioNTech vaccine (BNT162b2). The size of the study allowed for stratified analyses based on demographic characteristics and comorbidities. While neutralization assays were only completed for a subset of the study population, this segment of the cohort was enriched to include higher proportions of older participants and those with underlying comorbidities, to represent the general population more accurately.


The study population was composed solely of healthcare workers, who may not be demographically representative the general population. Participants who failed to complete the computer-based survey (n= 1,060, 22%) were excluded from the mixed-model analysis, although this behavior may not have been entirely random. Neutralizing antibody titers were measured using a pseudovirus-based assay rather than one using live virus. Neutralization assays were only completed for a subset of the study population (n=1,269, 26%). All neutralization assays were completed in the absence of other important components of the immune system (i.e., complement, T-cells) whose effector functions may remain intact despite reductions in antibody levels. Threshold titers required to prevent breakthrough infection have not yet been defined, and levels reported here may still be sufficient for protection. Researchers failed to assess the relationship between lower antibody levels/neutralization titers and breakthrough infection during the study.

Value added

This study provides a first look at the long-term durability of antibody responses after two doses of the Pfizer BioNTech SARS-CoV-2 vaccine (BNT162b2), using longitudinal samples collected from a large population of healthcare workers in Israel up to six months following vaccination.

This review was posted on: 18 October 2021