The update below is Section 7 of our "Guidance on Coronavirus Disease 2019 (COVID-19) for Transplant Clinicians"

TID COVID-19 Guidance Focused Review: SARS-CoV-2 Vaccines in Transplant Recipients

Date of Update: August 20, 2021

KEY POINTS

  • Transplant recipients may be vaccinated with any of the authorized or approved COVID-19 vaccines.
  • All transplant recipients should receive the vaccine, irrespective of past COVID-19 infection or positive SARS CoV-2 antibodies.
  • For SOT recipients, the ideal timing of vaccination is uncertain in the post-transplantation setting.
    • Vaccination should be delayed at least one month after transplant surgery or rejection treatment.
    • Longer delays may be required for patients who have received anti-B (i.e. rituximab) or anti-T cell (anti-thymocyte globulin, alemtuzumab). 
    • A risk-benefit assessment should weigh the community transmission risks against the likelihood of side effects.
  • For HSCT, in regions with accelerated transmission rates, COVID-19 vaccination may start at the 3rd month of HSCT. In regions where the risk of community acquisition of Covid-19 is lower, it is reasonable to wait until the sixth month after HSCT when better vaccine response is expected.
  • Organ donors who have received any COVID-19 vaccine may be used irrespective of time since vaccine; no vaccine would rule out a donor.
  • SOT and HSCT candidates should also receive the COVID-19 vaccine.
    • The concomitant administration of COVID-19 vaccines with other vaccines is considered safe.
    • Organ offers for candidates who have been recently vaccinated or are between doses 1 and 2 should generally proceed to transplant.  The persistence of protection has not been studied.  Doses post-transplant should be delayed at least 1-month post-transplant.
  • Household contacts of transplant recipients should be vaccinated to improve ring protection of the recipient and reduce the risk of transmission within the household.
  • We do not recommend routine adjustment of immunosuppressive medications before vaccination.
  • We do not recommend checking antibody responses to the vaccine.
  • We do recommend each center to develop approaches to educate patients on the importance of vaccination and consider tracking vaccination rates.
  • A third-dose booster of mRNA COVID-19 vaccine should be considered, where allowed by local regulatory approval. There is insufficient data to recommend boosters of patients who have not received mRNA vaccines at this time.
Transplant recipients who have received the COVID-19 vaccine should continue to observe all current preventive measures, such as masking, hand hygiene and safe distancing. 

Introduction

So far, 10 different platforms have been used in the development of these vaccines: 1) protein subunit (PS); 2) inactivated virus (IV); 3) non-replicating viral vector (VVnr); 4) RNA; 5) DNA; 6) virus-like particle (VLP); 7) replicating viral vector (VVr); 8) live attenuated virus (LAV); 9) VVnr + antigen-presenting cell (APC); and 10) VVr + APC.

To date, 21 SARS-CoV-2 vaccines have been authorized in several countries for emergency use (mRNA:  Pfizer/ BioNTech, Moderna; Viral Vector:  CanSino, Gamaleya Sputnik Light & Sputnik V, Janssen/Johnson & Johnson, AstraZeneca/Oxford, Serum Institute of India Covishield; DNA:  Zydus Cadila; Inactivated: Sinopharm, Sinovac CoronaVac, Sinopharm (Wuhan), Chumakov Center KoviVac, Bharat Biotech Covaxin, Kazakhstan RIBSP QazVac, Minhai Biotechnology, Shifa Pharmed Industrial; Protein Subunit:  FBRI EpiVacCorona, Center for Genetic Engineering and Biotechnology (CIGB),  Anhui Zhifei Longcom RBD-Dimer).  Vaccine role out has progressed considerably but continues to lag in low- and middle-income countries. In the healthy population, projected clinical efficacy based on phase 2 and phase 3 studies varies from more than 50% to 95%.1-9

Despite the achievements in such a short time, many questions remain unanswered, such as the titers of neutralizing antibodies for a COVID-19 vaccine to protect humans, the duration of vaccine-induced immunity, and the need for booster vaccines. These and other queries that may arise with the expanded use of the COVID-19 vaccines will likely be clarified over time.

COVID-19 vaccines in transplant recipients
While prioritization of vaccines is generally determined by the federal, state and local health authorities, transplant recipients should be included in groups for earlier vaccination due to the risk for severe COVID-19. Immunocompromised patients, including transplant recipients, have not been included in studies performed to date.  As these are not live virus vaccines, it is unlikely that these vaccines would pose additional risks. Transplant recipients may have decreased vaccine responses compared to the general population, and thus should be advised regarding the importance of maintaining all current guidance to protect themselves even after vaccination, including continuing to use masks, focus on hand hygiene and social distancing. Additionally, caregivers and household contacts should be strongly encouraged to get vaccinated when available to them to protect the patient.

Inactivated vaccines, protein subunit recombinant or virus-like vaccines are considered safe to be administered to transplant populations. Particle vaccines have been used for decades in transplant vaccination programs (e.g., influenza, hepatitis B and HPV vaccines). RNA vaccines (BioNTech/Pfizer, Moderna) and non-replicating viral vector vaccines (Oxford/AstraZeneca, Janssen/Johnson & Johnson, Gamaleya) are also considered safe vaccines, but have never been used in the transplant scenario. Vigilance will be necessary to determine if the induced protective immunity is not associated with an increased risk for rejection episodes or the development of graft versus host disease (GVHD).

Preliminary data of 741 SOT recipients who received both doses of mRNA SARS-CoV-2 vaccine doses has recently provided early insight into the safety and efficacy of the mRNA vaccine in this population.10 Equal numbers of recipients received the Pfizer and Moderna vaccines and had low rates of local (84% after dose 1 and 77% after dose 2and systemic (overall:  49% after dose 1 and 69% after dose 2; fatigue 36% after dose 1 and 56% after dose 2; headache 28% after dose 1 and 42% after dose 2) reactions.  Only 1 patient developed acute rejection following the second dose of vaccine.11-12

Unlike live virus vaccines, Adenovirus-vector vaccines have been genetically engineered to not replicate, and therefore cannot cause Adenovirus infection in the recipient. Based on the mechanism of action, expert opinion is that this vaccine is unlikely to trigger rejection episodes or have a novel or more severe side effects in transplant recipients, but more data are needed.

Live attenuated vaccines are generally contraindicated in SOT recipients and may be used with restrictions in HSCT recipients. Replicating viral vector vaccines are not recommended in transplant populations at this moment.

Several early studies have looked at the serologic response to the mRNA vaccines in SOT recipients.  Detectable antibodies have been demonstrated to be relatively infrequent after the first dose but detectable in up to 54% of patients after both doses of the vaccine.  When quantitative titers were available, they were frequently below the median titer in immunocompetent patients. However, the level of protective antibodies has not yet been defined. Furthermore, the protective components of both Cellular (T and NK T cells) and humoral responses (IgG/IgM or IgA) may not be linked in individual SOT recipients, and it is possible to still have an active acquired immune response in the absence of antibody and vice versa.  In fact, 46% of patients with a negative anti-RBD can have a positive CD4+ T cell response 13. Hence, the rate of breakthrough and severity of breakthrough infections based on antibody or cellular response has not been fully studied to inform the clinical efficacy of the vaccine in the transplant population.11, 14-18 

While there have been some observational cohort studies of transplant patients who have received a third dose of vaccine, either through government-approved channels or through other unapproved pathways, only one study to date has been a prospective, placebo-controlled study.13  In this trial, a third dose of vaccine was associated with a higher rate of patients having a pre-defined anti-RBD antibody level of at least 100 U per milliliter (33/60, 55% mRNA-1273 group vs. 10/57, 18% placebo), higher rate of neutralizing antibody titer and greater frequency of SARS-CoV-2 specific CD4+ T cell counts (432 vs. 67 cells per 106).  There is no data yet on the impact of a third dose of vaccine on important clinical measures, including frequency and severity of COVID-19 of breakthrough infections.  Likewise, it is important to note that 45% of patients failed to have a relevant antibody response even after 3 doses.  Since seroprotective titers have yet to be established this may be an underestimate of the population still at risk for breakthrough infections.  There is limited data on the utility of boosting with other vaccine times.  While the larger studies suggest have demonstrated the safety of boosting with the same vaccine as the initial series, a recent study showed that BNT162b2 given as a second dose in individuals prime vaccinated with ChAdOx1-S (transplant recipients were not included), induced a robust immune response with an acceptable and manageable reactogenicity profile.19

Since humoral and cellular responses to vaccine, even with 3 doses, are reduced in immunocompromised patients, additional mitigation strategies should be continued post-vaccine and additional studies of alternative protective approaches are needed.

There is emerging data on the benefit of the vaccine on transplant patients.  The best data to date comes from the UK NHS Blood & Transplant group.  In their retrospective review of registry data, 82% of English transplant recipients were fully vaccinated by July 9, 2021.  Unadjusted data demonstrated a reduction in the frequency of breakthrough infections (3,473 in the unvaccinated vs. 143 in fully vaccinated) and case-fatality (438 deaths (12.6%) vs. 11 deaths (7.7%)) were lower in the vaccinated population.20  Similarly single-center clinical effectiveness data demonstrates an almost 80% reduction of symptomatic COVID-19 in vaccinated compared to unvaccinated SOT recipients.21

There are still limited studies on the efficacy of vaccines against SARS-CoV-2 in HSCT. A recent study of 857 patients with hematological malignancies showed a lower median anti-S1 IgG antibody responses after two BNT162b2 vaccine doses in these patients than in healthcare workers of the same age group. Patients who are actively treated with BTKIs, ruxolitinib, venetoclax, or anti-CD20 antibody therapies seem to be the most negatively affected and might be left unprotected from SARS-CoV-2 infection. Surprisingly, patients who received autologous HSCT or allogeneic HSCT were among the subgroups with the highest responses to the SARS-CoV-2 vaccine, in comparison with other hematological patients.22

Given the existing data, it is essential that transplant programs provide education about the benefits and safety of the vaccine in transplant patients and strongly encourage vaccination.  They should also remind patients that, given the limitations of vaccines in this population, even among patients who receive a third dose, they should continue to maintain the use of masks in public indoor spaces, maintain social distancing, and avoid high-risk exposures.  Further, vaccination of close contact of our immunocompromised patients will reduce the risk of transmission of COVID-19 within a household.23


Table 1.  Vaccines with EUA Approval or Advanced Development


Vaccine

Type

Interval Between Doses

Vaccine Efficacy

Storage

EUA

Pfizer/BioNTech

mRNA

21 days

95%

-70°C

US, UK, EU, Switzerland, Saudi Arabia, other

Moderna

mRNA

28 days

94.5%

-20°C

US, UK, EU, other

Sputnik V

Ad26/Ad5

21 days

91.4%

2-8°C

Russia, Others

AstraZeneca

ChAdOx1

28 days

60-85%

2-8°C

UK, India, Others

Johnson & Johnson

Ad26

1 dose

57-72%

2-8°C

US and Others

Cansino

Ad5

1 dose

66%

2-8°C

China

Sinopharm

Inactivated

21 days

79.6-86%

2-8°C

China, UAE, Bahrain, Egypt, Jordan

Sinovac

Inactivated

14 days

50.1%

2-8°C

China, Brazil

Sinopharm-Wuhan

Inactivated

14 days

72.5%

2-8°

China, UAE

Bharat

Inactivated

28 days

93.4%

2-8°C

India

Novovax

Protein+

21 days

60-90%

2-8°C

Pending

None of the above vaccines are live virus vaccines or replication-competent viral vectors; all may be used in transplant recipients, candidates or donors.


References:

  1. Baden LR, El Sahly HM, Essink B, et al. Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine. N Engl J Med. 2020.
  2. Logunov DY, Dolzhikova IV, Zubkova OV, et al. Safety and immunogenicity of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine in two formulations: two open, non-randomised phase 1/2 studies from Russia. Lancet. 2020;396(10255): 887-897.
  3. Voysey M, Clemens SAC, Madhi SA, et al. Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK. Lancet. 2020.
  4. Zhang Y, Zeng G, Pan H, et al. Safety, tolerability, and immunogenicity of an inactivated SARS-CoV-2 vaccine in healthy adults aged 18-59 years: a randomised, double-blind, placebo-controlled, phase 1/2 clinical trial. Lancet Infect Dis. 2020.
  5. Logunov DY, Dolzhikova IV, Zubkova OV, et al. Safety and immunogenicity of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine in two formulations: two open, non-randomised phase 1/2 studies from Russia. Lancet. 2020;396(10255): 887-897.
  6. Zhu FC, Guan XH, Li YH, et al. Immunogenicity and safety of a recombinant adenovirus type-5-vectored COVID-19 vaccine in healthy adults aged 18 years or older: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet. 2020;396(10249): 479-488.
  7. Ramasamy MN, Minassian AM, Ewer KJ, et al. Safety and immunogenicity of ChAdOx1 nCoV-19 vaccine administered in a prime-boost regimen in young and old adults (COV002): a single-blind, randomised, controlled, phase 2/3 trial. Lancet. 2021;396(10267): 1979-1993.
  8. Wu Z, Hu Y, Xu M, et al. Safety, tolerability, and immunogenicity of an inactivated SARS-CoV-2 vaccine (CoronaVac) in healthy adults aged 60 years and older: a randomised, double-blind, placebo-controlled, phase 1/2 clinical trial. Lancet Infect Dis. 2021.
  9. Xia S, Zhang Y, Wang Y, et al. Safety and immunogenicity of an inactivated SARS-CoV-2 vaccine, BBIBP-CorV: a randomised, double-blind, placebo-controlled, phase 1/2 trial. Lancet Infect Dis. 2021;21(1): 39-51.
  10. Ou MT, Boyarsky BJ, Motter JD, et al. Safety and Reactogenicity of 2 Doses of SARS-CoV-2 Vaccination in Solid Organ Transplant Recipients. Transplantation. 2021.
  11. Boyarsky BJ, Werbel WA, Avery RK, et al. Antibody Response to 2-Dose SARS-CoV-2 mRNA Vaccine Series in Solid Organ Transplant Recipients. JAMA. 2021;325(21): 2204-2206.
  12. Del Bello A, Marion O, Delas A, Congy-Jolivet N, Colombat M, Kamar N. Acute rejection after anti–SARS-CoV-2 mRNA vaccination in a patient who underwent a kidney transplant. Kidney International. 2021;100(1): 238-239.
  13. Hall VG, Ferreira VH, Ku T, et al. Randomized Trial of a Third Dose of mRNA-1273 Vaccine in Transplant Recipients. N Engl J Med. 2021.
  14. Wadei HM, Gonwa TA, Leoni JC, Shah SZ, Aslam N, Speicher LL. COVID-19 infection in solid organ transplant recipients after SARS-CoV-2 vaccination. American Journal of Transplantation.n/a(n/a).
  15. Benotmane I, Gautier-Vargas G, Cognard N, et al. Low immunization rates among kidney transplant recipients who received 2 doses of the mRNA-1273 SARS-CoV-2 vaccine. Kidney International.
  16. Rabinowich L, Grupper A, Baruch R, et al. Low immunogenicity to SARS-CoV-2 vaccination among liver transplant recipients. J Hepatol. 2021.
  17. Grupper A, Rabinowich L, Schwartz D, et al. Reduced humoral response to mRNA SARS-CoV-2 BNT162b2 vaccine in kidney transplant recipients without prior exposure to the virus. Am J Transplant. 2021.
  18. Peled Y, Ram E, Lavee J, et al. BNT162b2 vaccination in heart transplant recipients: Clinical experience and antibody response. J Heart Lung Transplant. 2021: S1053-2498(1021)02274-02279.
  19. Borobia AM, Carcas AJ, Perez-Olmeda M, et al. Immunogenicity and reactogenicity of BNT162b2 booster in ChAdOx1-S-primed participants (CombiVacS): a multicentre, open-label, randomised, controlled, phase 2 trial. Lancet. 2021;398(10295): 121-130.
  20. Ravanan R, Mumford L, Ushiro-Lumb I, et al. Two Doses of SARS-CoV-2 Vaccines Reduce Risk of Death Due to COVID-19 in Solid Organ Transplant Recipients: Preliminary Outcomes From a UK Registry Linkage Analysis. Transplantation. 2021.
  21. Aslam S, Adler E, Mekeel K, Little SJ. Clinical effectiveness of COVID-19 vaccination in solid organ transplant recipients. Transpl Infect Dis. 2021: e13705.
  22. Maneikis K, Sablauskas K, Ringeleviciute U, et al. Immunogenicity of the BNT162b2 COVID-19 mRNA vaccine and early clinical outcomes in patients with haematological malignancies in Lithuania: a national prospective cohort study. Lancet Haematol. 2021;8(8): e583-e592.
  23. Harris RJ, Hall JA, Zaidi A, Andrews NJ, Dunbar JK, Dabrera G. Effect of Vaccination on Household Transmission of SARS-CoV-2 in England. N Engl J Med. 2021;385(8): 759-760.

 

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