Researchers compare immune responses elicited by three COVID-19 vaccines after eight months

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Based on the strength of clinical trial data showing the vaccines conferred robust protection against COVID-19, the U.S. Food & Drug Administration granted emergency use authorization to the mRNA-based vaccines known as BNT162b2 (BioNTech, Pfizer) and mRNA-1273 (Moderna) in December 2020, and to the Ad26.COV2.S (Johnson & Johnson) single-shot vaccine in February 2021. To date, nearly 200 million Americans have received a COVID-19 vaccine, and as some approach the one-year anniversary of their immunization, questions remain about the vaccines’ long-term efficacy.

In a paper published in the New England Journal of Medicine, a team of experts at Beth Israel Deaconess Medical Center (BIDMC) compared immune responses induced by the three vaccines over an eight-month follow-up period.

The investigators evaluated the 61 participants’ levels of various antibodies, T cells and other immune products at two to four weeks following complete immunization – the time of peak immunity – to eight months after vaccination. Thirty-one participants received the BNT162b2 vaccine, 22 received the mRNA-1273 vaccine and eight received the Ad26.COV2.S vaccine.

“The mRNA vaccines were characterized by high peak antibody responses that declined sharply by month six and declined further by month eight,” said corresponding author Dan H. Barouch, MD, Ph.D., director of the Center for Virology and Vaccine Research at BIDMC, who helped develop the Ad26 platform in collaboration with Johnson & Johnson.

“The single-shot Ad26 vaccine induced lower initial antibody responses, but these responses were generally stable over time with minimal to no evidence of decline.”

The team also found that mRNA-1273 elicited antibody responses which were generally higher and more durable than BNT162b2. All three vaccines demonstrated broad cross-reactivity to variants of SARS-CoV-2, the virus that causes COVID-19.

The findings have important implications for understanding how vaccine immunity may wane over time; however, the precise immune responses necessary to confer protection against SARS-CoV-2 has not yet been determined, the researchers point out.

“Even though neutralizing antibody levels decline, stable T cell responses and non-neutralizing antibody functions at 8 months may explain how the vaccines continue to provide robust protection against severe COVID-19,” said lead author Ai-ris Y. Collier, MD, a maternal-fetal medicine specialist at BIDMC. “Getting vaccinated (even during pregnancy) is still the best tool we have to end the COVID-19 pandemic.”


At peak immunity, the BNT162b2 vaccine induced a high median live-virus neutralizing antibody titer (1789), a high median pseudovirus neutralizing antibody titer (700), and a high median binding antibody titer against the receptor-binding domain (RBD) (21,564).

However, these titers declined sharply by 6 months after vaccination, as previously reported,1,2 and they declined further by 8 months (Figure 1A through 1C, S1, and S2). By 8 months after BNT162b2 vaccination, the median live-virus neutralizing antibody titer (53), pseudovirus neutralizing antibody titer (160), and RBD-specific binding antibody titer (755) elicited by the vaccine were lower than the peak titers by a factor of 34, 4, and 29, respectively.

At peak immunity, the mRNA-1273 vaccine also elicited a high median live-virus neutralizing antibody titer (5848), pseudovirus neutralizing antibody titer (1569), and RBD-specific binding antibody titer (25,677). By 8 months after mRNA-1273 vaccination, the median live-virus neutralizing antibody titer was 133, the pseudovirus neutralizing antibody titer was 273, and the median RBD-specific binding antibody titer was 1546; these titers were lower than the peak titers by a factor of 44, 6, and 17, respectively.

The Ad26.COV2.S vaccine induced substantially lower median titers than the mRNA vaccines at peak immunity. At 4 weeks after single-shot Ad26.COV2.S immunization, the median live-virus neutralizing antibody titer was 146, the median pseudovirus neutralizing antibody titer was 391, and the median RBD-specific binding antibody titer was 1361; however, these titers remained relatively stable over 8 months.3

At 8 months, the median live-virus neutralizing antibody titer was 629, the median pseudovirus neutralizing antibody titer was 185, and the median RBD-specific binding antibody titer was 843; these titers were similar to the titers at week 4. With all three vaccines, there were generally stable antibody-dependent cellular phagocytosis and antibody-dependent complement deposition responses (Fig. S3).

Recipients of the BNT162b2 and mRNA-1273 vaccines also had decreases in titers of live-virus neutralizing antibodies, pseudovirus neutralizing antibodies, and RBD- and spike protein (S)–specific binding antibody responses against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants from peak immunity to 8 months; after Ad26.COV2.S vaccination, however, there were stable or in some cases increasing antibody titers against these variants (Figs. S4 and S5).

At 8 months, the median pseudovirus neutralizing antibody titers against the SARS-CoV-2 B.1.617.2 (delta) variant were similar with the BNT162b2 vaccine (67), the mRNA-1273 vaccine (76), and the Ad26.COV2.S vaccine (107).

T-cell responses were assessed by CD4+ and CD8+ intracellular cytokine-staining assays that used pooled S peptides for stimulation (Figure 1D and 1E). At 8 months, the median CD8+ T-cell responses were 0.016% with the BNT162b2 vaccine, 0.017% with the mRNA-1273 vaccine, and 0.12% with the Ad26.COV2.S vaccine. With all three vaccines, T-cell responses showed broad cross-reactivity against SARS-CoV-2 variants (Fig. S6).

These data show differential kinetics of immune responses induced by the mRNA and Ad26.COV2.S vaccines over an 8-month follow-up period. As shown in previous studies,1,2 the BNT162b2 and mRNA-1273 vaccines were characterized by high peak antibody responses that declined sharply by 6 months; these responses declined further by 8 months.

Antibody titers in recipients of the mRNA-1273 vaccine were generally higher than those in recipients of the BNT162b2 vaccine. The Ad26.COV2.S vaccine induced lower initial antibody responses, but these responses were relatively stable over the 8-month follow-up period, with minimal-to-no evidence of decline.3 These findings have important implications for waning vaccine immunity, although correlates of protection from SARS-CoV-2 are not yet defined.

Figure 1. Kinetics of Humoral and Cellular Immune Responses Elicited by the BNT162b2, mRNA-1273, and Ad26.COV2.S Vaccines.
Shown are immune responses after vaccination with BNT162b2, mRNA-1273, and Ad26.COV2.S at peak immunity (2 to 4 weeks after the second dose in recipients of the messenger RNA vaccines or 4 weeks after one dose in recipients of the Ad26.COV2.S vaccine) and at 6 months, 8 months, or both after the first dose. Panel A shows the serum 50% inhibitory dilution (ID50) titers in the live-virus neutralizing antibody assay. Red bars indicate medians, dashed lines the limit of detection for each assay, and each dot a single participant. Panel B shows the serum dilution for 50% reduction (NT50) expressed in relative light units in the pseudovirus neutralizing antibody assay. Panel C shows the binding IgG antibody titers against the receptor-binding domain (RBD) in the serum enzyme-linked immunosorbent assay. Intracellular cytokine-staining assays were performed to measure the percentage of interferon-γ production in T cells; Panel D shows this percentage in CD4+ T cells, and Panel E shows this percentage in CD8+ T cells. Flow cytometric gating was performed to identify T cells (which are CD3+) rather than other CD4+- or CD8+-expressing immune cells. All assays were performed with the use of the SARS-CoV-2 WA1/2020 strain. The Ad26.COV2.S vaccine data in Panels B through E were published previously3 and are included here for comparative purposes.

More information: Ai-ris Y. Collier et al, Differential Kinetics of Immune Responses Elicited by Covid-19 Vaccines, New England Journal of Medicine (2021). DOI: 10.1056/NEJMc2115596

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