mRNA vaccines induce durable immune memory to SARS-CoV-2 and variants of concern

Immune memory after vaccination

Vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has proven highly effective at preventing severe COVID-19. However, the evolution of viral variants, and waning antibody levels over time, raise questions regarding the longevity of vaccine-induced immune protection. Goel et al. examined B and T lymphocyte responses in individuals who received SARS-CoV-2 messenger RNA vaccines. They performed a 6-month longitudinal study of individuals who never had SARS-CoV-2 infection compared with people who had recovered from SARS-CoV-2. Humoral and cellular immune memory was observed in vaccinated individuals, as were functional immune responses against the Alpha (B.1.1.7), Beta (B.1.351), and Delta (B.1.617.2) viral variants. Analysis of T cell activity suggested that robust cellular immune memory may prevent hospitalization by limiting the development of severe disease. —PNK

Abstract

Blood analysis of individuals vaccinated with the Moderna SARS-CoV-2 mRNA vaccine reveals distinct trajectories of immune memory responses.

Abstract

INTRODUCTION

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccines are highly effective at preventing infection and especially severe disease. However, the emergence of variants of concern (VOCs) and increasing infections in vaccinated individuals have raised questions about the durability of immunity after vaccination.

RATIONALE

To study immune memory, we longitudinally profiled antigen-specific antibody, memory B cell, and memory T cell responses in 61 individuals receiving mRNA vaccines from baseline to 6 months postvaccination. A subgroup of 16 individuals had recovered from prior SARS-CoV-2 infection, providing insight into boosting preexisting immunity with mRNA vaccines.

RESULTS

mRNA vaccination induced robust anti-spike, anti–receptor binding domain (RBD), and neutralizing antibodies that remained above prevaccine baseline levels in most individuals at 6 months postvaccination, although antibodies did decline over time. mRNA vaccination also generated spike- and RBD-specific memory B cells, including memory B cells that cross-bound Alpha, Beta, and Delta RBDs, that were capable of rapidly producing functional antibodies after stimulation. Notably, the frequency of SARS-CoV-2–specific memory B cells continued to increase from 3 to 6 months postvaccination. mRNA vaccines also generated a higher frequency of variant cross-binding memory B cells than mild SARS-CoV-2 infection alone, with >50% of RBD-specific memory B cells cross-binding all three VOCs at 6 months. These variant-binding memory B cells were more hypermutated than wild-type–only binding cells. SARS-CoV-2–specific memory CD4 ⁺ and CD8 ⁺ T cell responses contracted from peak levels after the second vaccine dose, with relative stabilization of SARS-CoV-2–specific memory CD4 ⁺ T cells from 3 to 6 months. T follicular helper cell responses after the first vaccine dose correlated with antibodies at 6 months, highlighting a key role for early CD4 ⁺ T cell responses. Finally, recall responses to mRNA vaccination in individuals with preexisting immunity led to an increase in circulating antibody titers that correlated with preexisting memory B cell frequency. However, there was no substantial increase in the long-term frequency of memory B and T cells. There was also no significant difference in the decay rates of antibodies in SARS-CoV-2–naïve versus –recovered subjects after vaccination, which suggests that the main benefit of recall responses to mRNA vaccination may be a robust but transient increase in circulating antibodies.

CONCLUSION

These findings demonstrate multicomponent immune memory after SARS-CoV-2 mRNA vaccination, with memory B and T cell responses remaining durable even as antibodies decline. Immune memory was resilient to VOCs and generated an efficient recall response upon antigen reexposure. These durable memory cells may be responsible for continued protection against severe disease in vaccinated individuals, despite a gradual reduction in antibodies. Our data may also inform expectations for the immunological outcomes of booster vaccination.

Immune memory after mRNA vaccination.

SARS-CoV-2–specific antibody, memory B, and memory T cell responses were measured at six time points after vaccination, highlighting a coordinated evolution of durable immunological memory. B cell memory was also resilient to VOCs and capable of producing new antibodies upon reactivation. IgG, immunoglobulin G; Ab, antibody; NTD, N-terminal domain; T _FH, T follicular helper cell; WT, wild-type.

Abstract

The durability of immune memory after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) messenger RNA (mRNA) vaccination remains unclear. In this study, we longitudinally profiled vaccine responses in SARS-CoV-2–naïve and –recovered individuals for 6 months after vaccination. Antibodies declined from peak levels but remained detectable in most subjects at 6 months. By contrast, mRNA vaccines generated functional memory B cells that increased from 3 to 6 months postvaccination, with the majority of these cells cross-binding the Alpha, Beta, and Delta variants. mRNA vaccination further induced antigen-specific CD4 ⁺ and CD8 ⁺ T cells, and early CD4 ⁺ T cell responses correlated with long-term humoral immunity. Recall responses to vaccination in individuals with preexisting immunity primarily increased antibody levels without substantially altering antibody decay rates. Together, these findings demonstrate robust cellular immune memory to SARS-CoV-2 and its variants for at least 6 months after mRNA vaccination.