Fatal breakthrough infection after anti-BCMA CAR-T therapy highlights suboptimal immune response to SARS-CoV-2 vaccination in myeloma patients

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines are highly effective in healthy individuals. Patients with multiple myeloma (MM) are immunocompromised due to defects in humoral and cellular immunity as well as immunosuppressive therapies. The efficacy after two doses of SARS-CoV-2 mRNA vaccination in MM patients is currently unknown. Here, we report the case of a MM patient who developed a fatal SARS-CoV-2 infection after full vaccination while in remission after B cell maturation antigen (BCMA)-targeted chimeric antigen receptor (CAR)-T treatment. We show that the patient failed to generate antibodies or SARS-CoV-2-specific B and T cell responses, highlighting the continued risk of severe coronavirus disease 2019 (COVID-19) in vaccine non-responders. In the largest cohort of vaccinated MM patients to date, we demonstrate that 15.9% lack SARS-CoV-2 spike antibody response more than 10 days after the second mRNA vaccine dose. The patients actively receiving MM treatment, especially on regimens containing anti-CD38 and anti-BCMA, have lower antibody responses compared to healthy controls. Thus, it is of critical importance to monitor this patient population for serological responses. Non-responders may benefit from ongoing public health measures and from urgent study of prophylactic treatments to prevent SARS-CoV-2 infection.

A correlate of protection for SARS-CoV-2 vaccines is urgently needed

“…Many individuals with a compromised immune system, including transplant patients, patients with cancer and individuals taking immunosuppressive drugs, do not mount strong responses to vaccines, including those for SARS-CoV-2 [5][6][7][8] . At present, the messaging from regulatory agencies states that "antibody tests should not be used to evaluate a person's level of immunity or protection from COVID-19. "…”

“…Mechanistically, the induction of strong antibody responses is dependent on CD4 + T cell responses, and there are preliminary reports of immunocompromised individuals who did not mount antibody responses to vaccination against SARS-CoV-2 and subsequently succumbed to infection 5 . Having an established correlate of protection would allow healthcare providers to manage the vaccination of immunocompromised individuals more efficiently, such as by recommending booster vaccinations if antibody titers are too low, or recommending non-pharmaceutical interventions for protection if no immune response is detected.…”

SARS-CoV-2 mRNA Vaccine Response in People Living with HIV According to CD4 Count and CD4/CD8 Ratio

“…These findings confirm our hypothesis that, given the immune dysregulation that characterizes chronic HIV infection, despite effective ART, PLWH with a low CD4 count remain at risk of lower immune responses to SARS-CoV-2 vaccination, at least in the short term, with potentially negative implications for clinical outcomes. Mechanistically, it is known that the induction of strong antibody responses is dependent on both CD4+ and CD8+ T-cell responses, and there are reports of immunocompromised individuals, including PLWH, who did not mount antibody responses to vaccination against SARS-CoV-2 and subsequently became infected [5,8,[20][21][22][23][24][25].…”

Criteria for judging the immune markers of COVID‐19 disease vaccines

“…Researchers thus could use Abs titer to predict the efficacy mean of developing vaccines 57 . However, it is noteworthy that immunocompromised individuals, like patients with cancer, HIV, or organ transplant, may not have detectable Abs after vaccination 58–61 . We did not specifically analyze the situation when humoral immunity was suppressed, but some researchers pointed out that cellular immunity still worked for those individuals.…”

“…57 However, it is noteworthy that immunocompromised individuals, like patients with cancer, HIV, or organ transplant, may not have detectable Abs after vaccination. [58][59][60][61] We did not specifically analyze the situation when humoral immunity was suppressed, but some researchers pointed out that cellular immunity still worked for those individuals. The animal experiment demonstrated that cellular immunity, including CD8+ T cells, protected convalescent macaques with low-level Ab titer from the reinfection of SARS-CoV-2.…”