Two doses of COVID-19 BNT162b2 mRNA vaccine (Comirnaty) required to bring antibody levels above threshold of positivity in all age ranges

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While mRNA vaccines authorized for emergency use are administered worldwide to contain the COVID-19 pandemic, little is known about the heterogeneity of the humoral immune response they induce at the population scale.  Immune responses are known to deteriorate with age, as evidenced by the burden of infectious disease (Williamson et al., 2020) and impaired responses to vaccine challenges (Ciabattini et al., 2018) both higher in older people than in the general population. Hence, age is one of the factors expected to contribute to the variability of the immune response to COVID-19 vaccination.

To formally describe the dynamics of the antibody response elicited by novel mRNA vaccines in the general population, we follow two cohorts of individuals who received two doses of the BNT162b2 vaccine early in 2021, and who together cover an adult age range from 19 to 99 years. The cohorts comprised 1245 healthcare workers (HCW) with median age of 43 years, and 146 nursing home residents (NHR) with median age of 87 years. We here report the humoral immune response to the 1st and the 2nd dose.

 

Our Study Design:

Blood samples were collected before vaccination (t0), 3-5 weeks after the 1st dose (t1), and 3 weeks after the 2nd dose (t2) of BNT162b2 mRNA COVID-19 (Comirnaty, Pfizer/BioNTech), see Figure 1. Spike-specific IgG, IgM, and IgA were measured by a semi-automated in-house ELISA assay. Anti-RBD total Ig was also measured in the HCW group. 297 HCW and 28 NHR participants were lost to follow-up or were excluded due to a positive PCR result for SARS-CoV-2 during the study. 

Figure 1: Study design and representation of age and sex distribution.

 

Our Results:

We observed a large variation in the antibody response to the 1st vaccine dose. The 2nd vaccine dose normalized this variation and elicited robust IgG responses in all age strata. Notably, while the 1st dose resulted in IgG levels above the threshold of positivity in 89% of the HCW population, only 25% of the NHR tested positive for anti-Spike IgG at the same point (Figure 2). The 2nd dose increased the positivity to 100% in the HCW cohort and to 95% in the NHR cohort. Importantly, with the 2nd vaccine dose IgG titers increased more than 10-fold in both HCW and NHR cohorts. 

 

 Figure 2: Anti-spike IgG positivity after the 1st (left) and 2nd (right) doses of BNT162b2 mRNA vaccine.

 

Age Effect:

Stratification of the results by age revealed a negative effect of age on the IgG levels (see Figure 3) measured 3 weeks after the 1st dose (t1). The same effect was observed for anti-Spike IgM and for anti-RBD Ig. IgG levels were significantly lower in NHR participants than in the oldest HCW participants (aged 60-70 years), but there was no difference in IgG levels between the 70-85 and the 86-99 age groups in the NHR cohort. No age effect was observed for IgA levels.   

 

Figure 3: Anti-Spike IgG results post Pfizer/BioNTech vaccine. Left panel: Anti-spike IgG pre- (t0) and post- 1st (t1) and 2nd (t2) doses. Right panel: Anti-Spike IgG across age strata after 1st dose (t1).

Sex Effect:

Participants were 73-79% female, a sex bias expected in both HCW and NHR. While sex-based effects have been previously reported in response to COVID-19 vaccination, only minor differences were attributable to sex in our study: in the HCW age strata 60-69 males presented lower response to the 1st dose when compared to females, and a similar trend was evident in the NHR cohort but only in response to the 2nd dose. 

 

Non-Responders:

In both cohorts, we identified a total of 7 non-responders, defined as participants who did not reach anti-spike IgG positivity after 2 vaccine doses. The only non-responder in the HCW cohort received immunosuppressant medication, representing 0.1% of the total 948 naïve. Among the 6 non-responders in the NHR cohort, representing 5% of the total 118 participants, 3 were men and 3 women and lack of anti-Spike IgG positivity was neither associated with medication or frailty.


These results advocate for the interval between the two doses not to be extended as one single vaccine dose may not suffice to generate high anti-spike IgG levels, particularly in the elderly population. In addition, serological monitoring of elderly and immunosuppressed vaccinees is highly recommended.

 

Our publication can be accessed in the following Open Access link: https://doi.org/10.1038/s41467-021-27761-z

 

References:

  • Williamson, E.J., et al. Factors associated with COVID-19-related death using OpenSAFELY. Nature 584, 430-436 (2020).
  • Ciabattini, A., et al. Vaccination in the elderly: The challenge of immune changes with aging. Semin Immunol 40, 83-94 (2018).

 

 

Patricia Borges

Technician, IGC