More than 2 y into the COVID-19 pandemic, solid organ transplant (SOT) recipients remain vulnerable to infection. Better testing, therapeutics, and vaccination have improved their overall mortality from infection and led to less disruption in performing kidney transplants.1 Nonetheless, SOT recipients face hurdles in returning to regular life activities given diminished vaccine efficacy in this population, relating to their immune suppression and baseline comorbid conditions.
Early after vaccine implementation, it became apparent that immunocompromised hosts have an attenuated response after 1 and 2 vaccine doses, as was highlighted in multiple interventional and observational studies and was consistent regardless of the vaccine platform used. The use of a third dose as part of the primary vaccine series was recommended by the United States Centers for Disease Control and Prevention for immunocompromised hosts in August 2021.2 In this issue, Bailey et al3 synthesized a meta-analysis to examine the response to a third dose of mRNA SARS-CoV vaccine in immunocompromised transplant recipients and showed an increased humoral response to a third dose in solid organ transplant recipients; almost half of those who did not have a serologic response after 2 vaccine doses developed a response after a third one. The cellular immune response was similarly augmented with a third dose. The study included >1200 patients from a dozen studies that met preset inclusion criteria. Their work provides compelling evidence for the need of additional vaccines in immunocompromised hosts. This supports the current guidance from the Centers for Disease Control and Prevention, which recommends that SOT recipients receive a primary vaccination series of 3 doses of the mRNA vaccine, followed by a first booster (fourth dose) and second booster (fifth dose) 3 and 4 mo after the third dose, respectively as well as another booster with the bivalent mRNA vaccine. ref: https://www.cdc.gov/vaccines/covid-19/clinical-considerations/interim-considerations-us.html#immunocompromised, accessed 6 October 2022.4 The World Health Organization currently recommends 1 booster shot in addition to the triple vaccine primary series for immunocompromised patients.5
The Omicron variant caused an intense and somewhat lethal surge in COVID-19 cases worldwide near the end of 2021. New subvariants continue to evolve and sublineages are emerging with increased immune evasion from both disease and vaccine-acquired immunity. Receipt of additional mRNA vaccine doses decreased the risk of Omicron variants COVID-19 associated hospitalization rates and disease severity in immunocompetent hosts with the risk further attenuated after 4 doses compared with 3 doses.4 Among SOT recipients, case series have shown an improved neutralizing antibody level after 4 vaccine doses. In 1 series, the improvement in humoral response to a fourth vaccine dose was seen in 41.9% of those who did not respond to 3 doses.6 In another series, 89% of 128 SOT recipient developed a serologic response after a fourth vaccine dose, with 61% of previously seronegative patients developing detectable immunity.7 Although the meta-analysis by Bailey et al supports 3 doses as the primary series, additional doses are clearly needed, especially for longer-term protection.
Given the blunted immune response to vaccination in SOTR, preexposure prophylaxis with tixagevimab/cilgavimab is being increasingly used, and it has shown effectiveness in reducing breakthrough infections with the Omicron variant.8 The in vitro activity of the monoclonal antibodies cocktail was maintained against the BA.5 sublineage in a recent study.9,10 Immune escape, however, via selective pressure from monoclonal antibody exposure could lead to the emergence of new variants in immunocompromised hosts, especially those with prolonged COVID-19 infections.11
Serious adverse events after additional mRNA vaccine booster continue to be rare, and according to the Vaccine Adverse Event Reporting System, a US safety surveillance system to monitor adverse events after vaccination, studying adverse events between January and March 2022, a time period in which about 500 000 immunocompromised hosts received a fourth shot, 4015 subjects registered through the system, and only 17 serious adverse events were reported.12 From the immunological adverse events standpoint, vaccines are very well tolerated by transplant recipients, and in general, events such as rejection or clinically significant de novo donor-specific antibodies formation13 are not associated with vaccination. Specific to COVID-19 vaccination, except for case reports describing allograft rejection in isolated cases, no widespread or significantly increased risk in allograft rejection has been described. Several studies looking at the immunogenicity of a third COVID shot in immunocompromised host showed no increased risk in allograft rejection. The work by Bailey et al in this issue highlights this as no acute rejection episodes were reported in the studies examined.
Multipronged approaches will continue to be needed in SOT recipients to prevent or diminish COVID-19 infection. When possible, the optimal strategy starts with primary vaccination before organ transplant, when vaccine efficacy is at its highest, followed by timely vaccine booster doses posttransplant. Such an approach supports the pretransplant COVID-19 vaccine mandates that were implemented at many transplant centers, as a best method to prevent severe COVID-19 infections. For those SOT recipients who underwent transplant before the vaccines were available, utilization of multiple doses of vaccine for the primary series followed by periodic boosters, along with preexposure prophylaxis monoclonal antibody, provides the safest and most effective method to prevent severe, life-threatening COVID-19. Moving forward, SOT recipients will likely need additional doses of vaccine, optimally tailored to actively circulating strains, such as the bivalent vaccines. We encourage the transplant community to keep SOT recipients up to date with their vaccines and preexposure prophylaxis monoclonal antibodies, along with methods for optimal infection control, to provide the best protection possible against this ongoing scourge.
1. Nimmo A, Gardiner D, Ushiro-Lumb I, et al. The global impact of COVID-19 on solid organ transplantation: two years into a pandemic. Transplantation. 2022;106:1312–1329.
2. Mbaeyi S, Oliver SE, Collins JP, et al. The advisory committee on immunization practices’ interim recommendations for additional primary and booster doses of covid-19 vaccines—United States, 2021. MMWR Morb Mortal Wkly Rep. 2021;70:1545–1552.
3. Bailey AJM, Maganti HB, Cheng W, et al. Humoral and cellular response of transplant recipients to a third dose of mRNA SARSCoV-2 vaccine: a systematic review and meta-analysis. Transplantation. 2023;107:204–215.
4. Centers for Disease Control and Prevention. Interim clinical considerations for use of COVID-19 vaccines currently approved or authorized in the United States.
July 20, 2022. Available at https://www.cdc.gov/vaccines/covid-19/clinical-considerations/interim-considerations-us.html#immunocompromised
. Accessed October 6, 2022.
5. World Health Organization. Interim statement on the use of additional booster doses of Emergency Use Listed mRNA vaccines against COVID-19.
May 17, 2022. Available at https://www.who.int/news/item/17-05-2022-interim-statement-on-the-use-of-additional-booster-doses-of-emergency-use-listed-mrna-vaccines-against-covid-19
. Accessed August 1, 2022.
6. Kamar N, Abravanel F, Marion O, et al. Assessment of 4 doses of SARS-CoV-2 Messenger RNA-based vaccine in recipients of a solid organ transplant. JAMA Netw Open. 2021;4:e2136030.
7. Mitchell J, Alejo JL, Chiang TPY, et al. Antibody response to a fourth dose of SARS-CoV-2 Vaccine in solid organ transplant recipients: an update. Transplantation. 2022;106:e338–e340.
8. Al Jurdi A, Morena L, Cote M, et al. Tixagevimab/cilgavimab pre-exposure prophylaxis is associated with lower breakthrough infection risk in vaccinated solid organ transplant recipients during the omicron wave [Online ahead of print]. Am J Transplant 2022. doi: 10.1111/ajt.17128.
9. Touret F, Baronti C, Pastorino B, et al. In vitro activity of therapeutic antibodies against SARS-CoV-2 Omicron BA.1, BA.2 and BA.5. Sci Rep. 2022;12:12609.
10. Takashita E, Yamayoshi S, Simon V, et al. Efficacy of antibodies and antiviral drugs against omicron BA.2.12.1, BA.4, and BA.5 subvariants. N Engl J Med. 2022;387:468–470.
11. Scherer EM, Babiker A, Adelman MW, et al. SARS-CoV-2 evolution and immune escape in immunocompromised patients. N Engl J Med. 2022;386:2436–2438.
12. Hause AM, Baggs J, Marquez P, et al. Safety monitoring of COVID-19 mrna vaccine first booster doses among persons aged ≥12 years with presumed immunocompromise status—United States, January 12, 2022-March 28, 2022. MMWR Morb Mortal Wkly Rep. 2022;71:899–903.
13. Mulley WR, Dendle C, Ling JEH, et al. Does vaccination in solid-organ transplant recipients result in adverse immunologic sequelae? A systematic review and meta-analysis. J Heart Lung Transplant. 2018;37:844–852.