Is Third Time the Charm? SARS-CoV-2 Vaccination in solid organ transplant recipients

Reviewed by Hannah Imlay, MD, MS; University of Utah and Erica Stohs, MD, MPH; University of Nebraska

Data mounts for a 3rd dose of an mRNA vaccine against SARS-CoV-2 in solid organ transplant recipients (SOTRs) prompting the FDA to expand emergency use authorization for Pfizer and Moderna vaccines and the CDC’s Advisory Council on Immunization Practices to update recommendations to allow an additional dose for SOTRs and comparably immunocompromised individuals. 

Following initial authorization of SARS-CoV-2 vaccines, several SOTR cohorts demonstrated suboptimal vaccine responses, typically measured by a low proportion or low quantitative levels of anti-spike antibody responses. Relative to antibody responses in the 90-95% range among healthy comparators, only 10-55% of SOTRs developed antibody responses after 2 doses of mRNA vaccination. 

Despite a low proportion of SOTRs who develop an antibody response, some data suggest that T-cell responses may be present, and that clinical vaccine effectiveness may be higher than what is represented by presence of anti-spike antibodies alone. Cucchiari et al. demonstrated that 30% of their SOTR cohort developed anti-spike antibodies and another 35% developed T cell responses measured by ELISPOT. Aslam et al. demonstrated almost 80% reduction in incidence of symptomatic COVID-19 among vaccinated vs unvaccinated SOTRs. 

Observational, single-arm studies by Kamar et al. and Benotmane et al. examined French SOTR cohorts who failed to mount a sufficient antibody response after 2 doses of SARS-CoV-2 mRNA vaccine and then received a 3rd dose of vaccine 1-2 months after the 2nd. They showed an increase in antibodies in 40-50%, suggesting that an additional dose may be beneficial among SOTRs. 

In a randomized controlled trial of a third dose of mRNA-1273 (Moderna) vs placebo among 120 SOTRs who received a primary 2-dose series, Hall et al. showed higher immune responses. The primary outcome, development of above-threshold anti-spike receptor binding domain antibody, occurred in a significantly higher proportion of the experimental vs placebo group (55% vs 18%). Secondary outcomes included neutralizing antibody responses and polyfunctional CD4+ T cell production, which were both higher in the experimental group. 

No cases of organ rejection were reported in the 3 studies examining a 3rd mRNA vaccine dose against SARS-CoV-2. The benefits of the 3-dose vaccine strategy in SOTRs appear to outweigh the risks, but is it the charm? Even with a 3rd dose, a substantial proportion of SOTRs still do not mount an antibody response following full vaccination—thus maintaining high-quality infection prevention practices (masking, distancing, etc.) is important. Expectedly, higher immunosuppression was associated with inadequate serologic response and how this translates to clinical effectiveness remains to be seen. 


Poor Immune Response in SOTRs: 

  • Aslam S, et al. Clinical effectiveness of COVID-19 vaccination in solid organ transplant recipients. Transpl Infect Dis. 2021 Jul 29:e13705. doi: 10.1111/tid.13705.
  • Cucchiari D, et al. Cellular and humoral response after MRNA-1273 SARS-CoV-2 vaccine in kidney transplant recipients. Am J Transplant. 2021 Aug;21(8):2727-2739. doi: 10.1111/ajt.16701.
  • Boyarsky BJ, et al. JAMA. 2021 Jun 1;325(21):2204-2206. doi: 10.1001/jama.2021.7489.

3rd dose in SOTRs:

  • Hall VG, et al. Randomized Trial of a Third Dose of mRNA-1273 Vaccine in Transplant Recipients. N Engl J Med. 2021 Aug 11. doi: 10.1056/NEJMc2111462.
  • Benotmane I, et al. Antibody Response After a Third Dose of the mRNA-1273 SARS-CoV-2 Vaccine in Kidney Transplant Recipients with Minimal Serologic Response to 2 Doses. JAMA. 2021 Jul 23. doi: 10.1001/jama.2021.12339.
  • Kamar N, et al. Three Doses of an mRNA Covid-19 Vaccine in Solid-Organ Transplant Recipients. N Engl J Med. 2021 Aug 12;385(7):661-662. doi: 10.1056/NEJMc2108861.
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