mRNA Vaccination Induces Durable Immune Memory to SARS-CoV-2 with Continued Evolution to Variants of Concern

Abstract

SARS-CoV-2 mRNA vaccines have shown remarkable efficacy, especially in preventing severe illness and hospitalization. However, the emergence of several variants of concern and reports of declining antibody levels have raised uncertainty about the durability of immune memory following vaccination. In this study, we longitudinally profiled both antibody and cellular immune responses in SARS-CoV-2 naive and recovered individuals from pre-vaccine baseline to 6 months post-mRNA vaccination. Antibody and neutralizing titers decayed from peak levels but remained detectable in all subjects at 6 months post-vaccination. Functional memory B cell responses, including those specific for the receptor binding domain (RBD) of the Alpha (B.1.1.7), Beta (B.1.351), and Delta (B.1.617.2) variants, were also efficiently generated by mRNA vaccination and continued to increase in frequency between 3 and 6 months post-vaccination. Notably, most memory B cells induced by mRNA vaccines were capable of cross-binding variants of concern, and B cell receptor sequencing revealed significantly more hypermutation in these RBD variant-binding clones compared to clones that exclusively bound wild-type RBD. Moreover, the percent of variant cross-binding memory B cells was higher in vaccinees than individuals who recovered from mild COVID-19. mRNA vaccination also generated antigen-specific CD8+ T cells and durable memory CD4+ T cells in most individuals, with early CD4+ T cell responses correlating with humoral immunity at later timepoints. These findings demonstrate robust, multi-component humoral and cellular immune memory to SARS-CoV-2 and current variants of concern for at least 6 months after mRNA vaccination. Finally, we observed that boosting of pre-existing immunity with mRNA vaccination in SARS-CoV-2 recovered individuals primarily increased antibody responses in the short-term without significantly altering antibody decay rates or long-term B and T cell memory. Together, this study provides insights into the generation and evolution of vaccine-induced immunity to SARS-CoV-2, including variants of concern, and has implications for future booster strategies.

Immune Memory Response After a Booster Injection of mRNA-1273 for Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2)

“…This higher level of antibody after the booster injection compared to the second injection is indicative of a robust immune memory response likely due to stimulation of memory B cells. [30][31][32][33] It is also important to note that the results here using a validated pseudovirus neutralization assay showed that the GMTs after the second dose of mRNA-1273 were higher at one month after the second dose in the 100 µg group (1268.0; 95% CI=1087.9, 1477.8) compared to the 50 µg group (629.2; 549.3, 720.8) (Figure 3; Supplementary Table 4).…”

Cellular and Humoral Immune Response to SARS-CoV-2 mRNA Vaccines in Patients Treated with either Ibrutinib or Rituximab

“…It suggested that the cellular response weakens through the time as it was raised by epidemiologic and immunological studies. [27][28][29][30] In conclusion our work shows that humoral immune response to SARS-CoV-2 vaccine is severely impaired in patients treated with Rituximab and Ibrutinib. Significant fraction of these patient mounts cellular immune response to the vaccine.…”

Covid-19 vaccination: evidence of waning immunity is overstated

“…From an immunological standpoint, plasma neutralising antibody titres are expected to decay eventually following vaccination, but robust and long lived plasmablast and germinal B cell responses have been shown after mRNA vaccination, and memory B cells have been shown to increase over at least six months, improve functionally, and provide cross-variant protection 1213. Plasma neutralising antibody titres may predict some level of protection from symptomatic infection.…”

“…Most importantly, the long term effect of boosters on reducing infection, transmission, and hospital admissions remains unknown. Although boosters increase plasma antibody levels and may temporarily extend antibody mediated protection, they have not been shown to augment the memory B and T cell responses expected to provide long term protection against severe disease for most immunocompetent people 16. In an observational study from Israel reporting benefit associated with a third dose of the Pfizer-BioNTech vaccine (BNT162b2),17 the follow-up period in the boosted group was just seven person days for severe disease and 12 person days for infection—too short to assess long term effectiveness.…”