Antibody responses in seropositive people after a single dose of SARS-CoV-2 mRNA vaccine

For the publisher:

The efficacy of two injections of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) peak messenger RNA (mRNA) vaccines (BNT162b2 [Pfizer] and mRNA-1273 [Moderna])¹ in the prevention of symptomatic SARS-CoV-2 infection in people without previous coronavirus disease in 2019 (Covid-19) was shown to be elevated.^2.3 We wondered what the response to the first dose of the vaccine would be in people with previous Covid-19.

We took advantage of our ongoing PARIS (SARS-CoV-2 Rapid Immunity Protection) study, approved by the institutional review board, to provide a limited snapshot of antibody responses in 110 study participants with or without pre-existing SARS-CoV- documented 2 immunity (general mean age, 40.0 years [range, 24 to 68; ≥60 years, 8%]; 67 seronegative participants [64% female] with an average age of 41.3 years and 43 seropositive participants [59% female] mean age 41.4 years) (Table S1 in the Supplementary Appendix, available with the full text of this letter at NEJM.org) who received their first dose of peak mRNA vaccine in 2020 (88 received the Pfizer vaccine and 22 Modern vaccine) The peak of SARS-CoV-2 IgG was measured using a previously described two-step enzyme-linked immunosorbent assay and expressed as area under the curve (AUC).^4.5

Figure 1. Figure 1. Immunogenicity and reactogenicity of SARS-CoV-2 RNA vaccines.

Panel A shows the quantitative SARS-CoV-2 peak antibody titers (assessed by enzyme-linked immunosorbent assay and expressed as an area under the curve [AUC]) for 110 participants. Some participants with pre-existing immunity had antibody titers below detection (AUC of 1) at the time point before vaccination. Geometric means with 95% confidence intervals (not adjusted for multiple tests) are shown. Panel B shows the relative frequency of side effects associated with the vaccine after the first dose of the vaccine (230 participants). Local side effects occurred with a similar frequency among participants with pre-existing immunity and among those without pre-existing immunity, while systemic symptoms were more common among participants with pre-existing immunity. The bars represent the relative frequency of each symptom and the numbers at the top of the graph represent the absolute numbers for a given symptom, with a particular participant possibly having more than one symptom.

Repeated sampling after the first dose indicates that most seronegative participants had variable and relatively low IgG SARS-CoV-2 responses 9 to 12 days after vaccination (median AUC before vaccination, 1 [67 participants]; from 0 to 4 days, 1 [12 participants]; in 5 to 8 days, 1 [22 participants]; from 9 to 12 days, 439 [13 participants]; in 13 to 16 days, 1016 [18 participants]; in 17 to 20 days, 1037 [21 participants]; from 21 to 27 days, 1293 [19 participants]; and after the second dose, 3316 [36 participants]) (Figure 1A) In contrast, participants with SARS-CoV-2 antibodies at baseline before the first vaccine injection rapidly developed high and uniform antibody titers within a few days after vaccination (median AUC before vaccination, 90 [43 participants]; from 0 to 4 days, 133 [7 participants]; in 5 to 8 days, 14,208 [15 participants]; from 9 to 12 days, 20,783 [8 participants]; in 13 to 16 days, 25,927 [20 participants]; in 17 to 20 days, 11,755 [4 participants]; from 21 to 27 days, 19,534 [14 participants]; and after the second dose, 22,509 [19 participants]) (Figure 1A)

The antibody titers of those vaccinated with pre-existing immunity were 10 to 45 times higher than those of those vaccinated without pre-existing immunity at the same time points after the first dose of the vaccine (for example, 25 times higher in 13 to 16 days) and also exceeded the median antibody titers measured in participants without pre-existing immunity after the second dose of vaccine by more than a factor of 6. Although the antibody titers of vaccinees without pre-existing immunity increased by a factor of 3 after the second dose of vaccine , no increase in antibody titers was observed in Covid-19 survivors who received the second dose of the vaccine. No substantial difference was observed in the dynamics of antibody responses induced by the Pfizer and Moderna vaccines after the first dose (Fig. S1). The current analysis represents a convenience sample in which not all participants were able to provide bio-specimens for antibody analysis at all additional time intervals. Follow-up studies in progress will show whether these initial differences in immune responses are maintained for an extended period of time.

In addition, we compared the frequency of local reactions, related to the injection site, as well as systemic reactions after the first dose of the vaccine in 230 participants (mean age, 39.2 years [range, 22 to 70; ≥60 years, 8%]; 148 seronegative participants [70% female] and 82 seropositive participants [64% female]) (Figure 1B) Overall, both vaccines (156 participants received the Pfizer vaccine and 74 the Modern vaccine) had no side effects that resulted in hospitalization. A total of 159 of the 230 participants (69%) who completed the survey in the PARIS study reported having some side effects after the first dose of the vaccine (46% of respondents in the seronegative survey and 89% of the respondents in the seropositive survey). The most common were symptoms located at the injection site (pain, swelling and erythema), which occurred with equal frequency, regardless of the serological status at the time of vaccination, and disappeared spontaneously a few days after vaccination. Recipients of the vaccine with pre-existing immunity had systemic side effects at higher frequencies than those without pre-existing immunity (fatigue, headache, chills, muscle pain, fever and joint pain, in order of decreasing frequency) (Figure 1B) As a convenience sample was used and only participants with available data were studied, caution is required until the entire data set, including side effects that occur after the first and second doses of the vaccine, can be assessed.

We found that a single dose of mRNA vaccine elicited rapid immune responses in seropositive participants, with similar or exceeded post-vaccination antibody titers in seronegative participants who received two vaccinations. If a single dose of mRNA vaccine offers effective protection in HIV-positive people, it is necessary to investigate.

Florian Krammer, Ph.D.
Komal Srivastava, MS
Hala Alshammary, MS
Angela A. Amoako, MS
Mahmoud H. Awawda, MS
Katherine F. Beach, BS
Maria C. Bermúdez-González, MPH
Dominika A. Bielak, BA
Juan M. Carreño, Ph.D.
Rachel L. Chernet, BA
Lily Q. Eaker, BA
Emily D. Ferreri, BS
Daniel L. Floda, BA
Charles R. Gleason, BS
Joshua Z. Hamburger, MD
Kaijun Jiang, MS
Giulio Kleiner, Ph.D.
Denise Jurczyszak, Ph.D.
Julia C. Matthews, BA
Wanni A. Mendez, AAS
Ismail Nabeel, MD
Lubbertus CF Mulder, Ph.D.
Ariel J. Raskin, BA
Kayla T. Russo, BS
Ashley-Beathrese T. Salimbangon, BA
Miti Saksena, MB, BS
Amber S. Shin, BS
Gagandeep Singh, Ph.D.
Levy A. Sominsky, BA
Daniel Stadlbauer, Ph.D.
Ania Wajnberg, MD
Viviana Simon, MD, Ph.D.
Icahn School of Medicine at Mount Sinai, New York, NY
[email protected], [email protected]

This letter was published on March 10, 2021, at NEJM.org.