Antibody responses in serositive individuals to a single dose of SARS-CoV-2 mRNA vaccine

To the editor:

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

We used our ongoing, long-term Paris study (protection associated with rapid immunity to SARS-CoV-2) to provide a limited snapshot of the antibody response in 110 study participants, whether or not with documented SARS-CoV-2 immunity (mean age, 40.0 years [range, 24 to 68; ≥60 years, 8%]; 67 seronegative participants [64% female] with a mean age of 41.3 years and 43 seropositive participants [59% female] with a mean age of 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 mRNA vaccine dose in 2020 (88 received the Pfizer vaccine received and 22 the Modern vaccine). SARS-CoV-2 peak 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 antibody pitters (assessed by enzyme-linked immunosorbent assay and expressed as area under the curve [AUC]) for 110 participants. Some participants with existing immunity had antibody titers under detection (AUC of 1) at the time before vaccination. Geometric means with 95% confidence intervals (not adjusted for multiple tests) are shown. Panel B shows the relative frequency of vaccine-related side effects after the first vaccine dose (230 participants). The local side effects occurred with the same frequency in participants with an existing immunity and among those who did not have an existing immunity, while the systemic symptoms were more common among participants with an 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 given participant possibly having more than one symptom.

Repeated sampling after the first dose indicates that the majority of seronegative participants had erratic and relatively low SARS-CoV-2 IgG responses within 9 to 12 days after vaccination (median AUC before vaccination, 1 [67 participants]; at 0 to 4 days, 1 [12 participants]; at 5 to 8 days, 1 [22 participants]; at 9 to 12 days, 439 [13 participants]; at 13 to 16 days, 1016 [18 participants]; at 17 to 20 days, 1037 [21 participants]; at 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 uniform, high antibody titers within a few days after vaccination (median AUC before vaccination, 90 [43 participants]; at 0 to 4 days, 133 [7 participants]; at 5 to 8 days, 14,208 [15 participants]; at 9 to 12 days, 20 783 [8 participants]; at 13 to 16 days, 25,927 [20 participants]; at 17 to 20 days, 11 755 [4 participants]; at 21 to 27 days, 19,534 [14 participants]; and after the second dose 22,509 [19 participants]) (Figure 1A).

The antibody titers of vaccinated with pre-existing immunity were 10 to 45 times as high as those of vaccinated without pre-existing immunity at the same time after the first vaccine dose (eg 25 times as high at 13 to 16 days) and also measured the median exceeded antibody titers at participants without pre-existing immunity after the second vaccine dose by more than a factor of 6. Although the antibody titers of the vaccinated without pre-existing immunity increased by a factor of 3 after the second vaccine dose, no increase in antibody titers was observed in the Covid-19 survivors received the second dose of vaccine. No significant difference was observed in the dynamics of antibody responses elicited by the Pfizer and Moderna vaccines after the first dose (Fig. S1). The present assay represents a convenience sample in which not all participants were able to produce bio-samples for antibody analysis with all the extra time intervals. Continuous follow-up studies will indicate whether these early differences in immune responses are maintained over a long period of time.

In addition, we compared the frequency of local, injection site-related as well as systemic reactions after the first dose of 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 Moderna vaccine) had no side effects leading to hospitalization. A total of 159 of the 230 participants (69%) who completed the PARIS study survey reported that they had some side effects after the first vaccine dose (46% of the respondents in the seregative survey and 89% of the respondents in the seropositive survey). Most common were localized symptoms at the injection site (pain, swelling and erythema), which occurred at the same frequency during vaccination, independent of the serostatus, and disappeared spontaneously within a few days after vaccination. Recipients of vaccines with pre-existing immunity have systemic side effects at higher frequencies than those without pre-existing immunity (fatigue, headache, chills, muscle aches, fever and joint pain, in descending order of frequency) (Figure 1B). Because a convenience sample was used and only participants with available data were studied, caution is required until the complete data set, including side effects occurring after the first as well as the second vaccine dose, can be assessed.

We found that a single dose of mRNA vaccine elicited rapid immune responses in seropositive participants, with antibody titers after vaccination that were similar to or greater than the titers found in seronegative participants who received two vaccinations. Whether a single dose of mRNA vaccine provides effective protection in seropositive individuals should be investigated.

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, Managing Director
Kaijun Jiang, MS
Giulio Kleiner, Ph.D.
Denise Jurczyszak, Ph.D.
Julia C. Matthews, BA
Wanni A. Mendez, AAS
Ismail Nabeel, Managing Director
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, Managing Director
Viviana Simon, MD, Ph.D.
Icahn School of Medicine at Mount Sinai, New York, NY
[email protected], [email protected]

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