Can COVID-19 vaccines be used by transplant patients?

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With the new coronavirus (COVID-19) vaccine on the market, more and more immigrants are concerned about whether they can use the COVID-19 vaccine? Here I combineThe American Society of Transplantation (AST) and the American Society of Hematology (ASH) recently released a FAQ on vaccine use.and other information, the issues that immigrant friends are concerned about are summarized as follows:

1.What COVID-19 vaccines are in development?

Vaccines currently under development can be divided according to type: nucleic acid vaccines, inactivated vaccines, replication-deficient adenovirus vector vaccines, attenuated vaccines and recombinant protein vaccines (Table 1)[1]:

Table 1: Vaccines under development and their progress

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Two nucleic acid-based vaccines (mRNA-1273 and BNT162b2) have received Emergency Use Authorization (EUA) from the U.S. Food and Drug Administration (FDA).

For real-time updates, follow: The New York Times Coronavirus Vaccine Tracker: https://www.nytimes.com/interactive/2020/science/coronavirus-vaccine-tracker.html; The Washington Post Vaccine Tracker: https://www.washingtonpost.com/graphics/2020/health/covid-vaccine-update-

2.When will it be officially available to transplant patients?

The Advisory Committee on Immunization Practices (ACIP) under the US CDC considers the following groups of people as candidates for the first phase of vaccination [2,3].

A. Medical staff

B. Patients who require long-term medical intervention in medical institutions

C. People at high risk of severe COVID-19 disease due to their special physical conditions

D. Elderly people over 65 years old E. People working in key areas of society

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Figure 1: Vaccination priorities proposed by ACIP

Transplant patients may belong to the category of "high-risk groups with the possibility of severe COVID-19 disease due to special physical conditions", and our country is also formulating a prioritization plan. Although it is still unclear exactly when the vaccine will be officially used,It can be expected that transplant patients may be included in early vaccination groups。

3.Is it safe for transplant patients?

The safety of vaccination for organ transplant patients is an issue worth considering. The FDA formulated strict safety standards in June this year. All vaccine candidates must meet safety and effectiveness standards. Vaccine safety includes both acute and long-term side effects associated with the vaccine.

3.1 Recombinant protein or inactivated vaccine:

Based on previous experience with other recombinant protein or inactivated virus-related vaccines, they have not shown specific side effects in patients with suppressed immune function [4]. Among themIn a study of influenza virus vaccines, it was shown that there was no increased risk of rejection in transplant patients, regardless of the use of standard doses of influenza vaccine or non-standard preparations (high-dose, adjuvanted vaccines) [5]。

Common acute side effects of both vaccines include: low-grade fever, myalgia, headache, nausea, fatigue and soreness/redness. In some trials, these acute side effects were more pronounced with booster doses. The long-term side effects are not yet known, and we need to wait for the long-term follow-up results of phase 3 clinical trials on healthy volunteers. According to EUA minimum standards, at least two months of safety assessment data are required from vaccination.

3.2 Attenuated vaccines

Live-attenuated vaccines carry the risk of transformation into pathogenic strains, which requires particular vigilance in immunosuppressed patients. It's unclear whether attenuated COVID-19 vaccines carry the same risks, butTheoretically, the use of live-attenuated vaccines in organ transplant patients should be avoided. Another risk of using live attenuated vaccines includes the potential spread of the virus to new areas where the vaccine is used. Manufacturers currently producing live attenuated COVID-19 vaccines are mainly in India and Türkiye.

3.3 Nucleic acid vaccine

Nucleic acid vaccines (mRNA vaccines) are a new type in the field of vaccines. Previously, mRNA-based and viral vector-based (usually adenovirus) vaccines were used for tumor treatment. Possible safety concerns with their use include the development of an excessive inflammatory response, which has been described in some animal models receiving adenoviral vector vaccines [6]. This effect has not been confirmed in humans. Another possible problem is that the type I interferon response caused by the mRNA vaccine increases, further causing autoimmune syndrome [7]. Therefore, organ transplant patients using mRNA vaccines may develop anti-COVID-19 antibodies leading to immune enhancement and systemic inflammatory responses similar to those seen in multisystem inflammatory syndrome in children (MIS-C).

The safety of nucleic acid vaccines in solid organ transplant patients remains under investigation.Based on theoretical derivation of their mechanism of action, experts believe that nucleic acid vaccines are unlikely to trigger rejection episodes., but more research data is needed to support it.

4.Effectiveness for use in transplant patients?

The effectiveness of the vaccine is another issue that transplant friends are concerned about, because the immune function is suppressed after transplantation, and whether the recommended dose of vaccine can effectively produce an immune response.

4.1 Recombinant protein or inactivated vaccine:

The efficacy of recombinant protein-based or inactivated COVID-19 vaccines in immunosuppressed patients remains to be studied. Existing data on the use of other inactivated virus vaccines have proven that they have certain efficacy in people with suppressed immune function [6]. When adjuvanted recombinant herpes zoster vaccine is administered 6 months after immunosuppressive therapy, patients can elicit strong humoral and cellular immune responses [8]. Influenza vaccines using inactivated virus can also elicit humoral immune responses in immunosuppressed patients (CLL), but response rates appear to be more variable, ranging from 15-63% in patients with CLL who are not actively treated, and falling to 7-26% in patients receiving BTK inhibitors (Iberatinib). The difference is that the immune response of the varicella-zoster vaccine and the influenza virus vaccine is partly a memory response.The immune response to COVID-19 will need to be developed from scratch, and little is known about how organ transplant patients will generate this response.。

Focus on effectiveness of COVID-19 vaccine use in transplant patients,Key considerations should be: blood routine changes, peripheral blood B and T cell immune phenotypes, immunoglobulin (IgG, IgM, IgA) quantification, etc.To determine whether the patient has developed a protective immune response. The impact of these factors on COVID-19 vaccine response is unknown.

4.2 Attenuated vaccines

Based on our limited knowledge of the safety risks of attenuated COVID-19 vaccines in transplant patients, the use of live attenuated vaccines in transplant patients should theoretically be avoided, and the effectiveness of attenuated viruses will not be discussed in detail here.

4.3mRNA vaccine

Pfizer and Moderna's mRNA vaccines have shown 94.1-95% efficacy in preventing infection with COVID-19 in people with normal immunity, and antibody titers persist for at least 4 months [9]. Durability data on vaccine titers are still under observation.

mRNAThe effectiveness of the vaccine in organ transplant patients needs further study. Transplant patients generally have lower antibody responses than non-transplant people. Data from previous studies have shown that the potency of conventional vaccines in serum gradually decreases after transplantation. Post-transplant protection may be reduced in patients who have been vaccinated before transplantation, especially if B-lymphocyte-depleting treatments are used (e.g., rituximab).

5.How are perioperative transplant patients vaccinated?

Based on previous vaccination guidelines for solid organ transplant patients, vaccination is recommended 2-4 weeks before transplantation or 1-6 months after transplantation, the influenza vaccine can be used within 1 month after transplantation [10]. Transplant patients and clinicians can weigh early protection and delayed vaccination as early as possible and choose the best opportunity to vaccinate.

6.If I have a history of COVID-19 infection, do I still need to get vaccinated?

Whether a transplant patient has a history of COVID-19 infection will not affect the decision to receive the vaccine. Although patients with a history of infection may acquire some immunity to COVID-19, this immunity may be insufficient or weakened [11,12]. The current principle is thatEveryone should be vaccinated regardless of past COVID-19 infection or evidence of prior humoral immunity.There are case reports showing that COVID-19 reinfection can occur in immunosuppressed patients [13], suggesting an appropriate immune response or decreased immunity after the first infection.

7.Are immunosuppressed people recruited into clinical trials?

There are currently no COVID-19 vaccine-related clinical trials enrolling patients receiving immunosuppressive therapy. Most trials require patients to stop immunosuppression for a certain period of time to be eligible, which is less feasible for patients who have already received a transplant.

8.Other matters

Benefits and harms: Although specific observational data for vaccines in transplant patients are currently lacking, benefits can be expected from vaccination. One reason includes that once infected with COVID-19, transplant patients appear to have clinically more severe infection outcomes than the general population [14]. Therefore,The benefits of vaccination outweigh any theoretical risks。

Dosage: There are no data supporting whether to increase the vaccine dose in immunosuppressed patients. But increasing the vaccine dose may increase side effects, similar to those seen with the second dose in a two-dose series. Measuring titers may ultimately help assess response, but more information is needed.The use of higher doses of COVID-19 vaccines is currently not recommended.

As the development of vaccine candidates and actual vaccination progress, some data will be updated, so please stay tuned.

References:

1. U.S.Department of Health and Human Services (HHS).BARDA’s Rapidly ExpandingCOVID-19 Medical Counter Measures 2020 [Availablefrom:https://www.medicalcountermeasures.gov/app/barda/coronavirus/COVID19.aspx?filter=vaccine.

2. Centers for Disease Control (CDC). Coronavirus Disease 2019 (COVID-19) 2020[Available from:https://www.cdc.gov/coronavirus/2019-ncov/hcp/vaccination.html.

3. Dooling K, McClung N, Chamberland M, et al. The Advisory Committee on Immunization Practices’ Interim Recommendation for Allocating Initial Supplies of COVID-19 Vaccine — United States, 2020. MMWR Morb Mortal Wkly Rep 2020;69:1857-1859. doi: http://dx.doi.org/10.15585/mmwr.mm6949e1

4. Rubin LG, Levin MJ, Ljungman P, et al. 2013 IDSA clinical practice guideline for vaccination of the immunocompromised host. ClinInfect Dis. 2014Feb;58(3):309-18. doi: 10.1093/cid/cit816.

5. Cédric Hirzel , Deepali Kumar. Influenzavaccine strategies for solid organ transplant recipients. 2018; 31(4):309-315.

6. BosR, Rutten L, van der Lubbe JEM, et al. Ad26 vector-based COVID-19 vaccine encoding a prefusion-stabilized COVID-19 Spike immunogen induces potenthumoral and cellular immuneresponses. NPJ Vaccines2020; 5:91. doi:10.1038/s41541-020-00243-x.

7. Pardi N, Hogan MJ, Porter FW, et al. Nat Rev DrugDiscov. 2018Apr;17(4):261-279. doi: 10.1038/nrd.2017.243.

8. Dagnew AF, Ilhan O, Lee WS, et al. Immunogenicityand safety of the adjuvanted recombinant zoster vaccine inadults with haematological malignancies: A phase3, randomised, clinical trialand post-hoc efficacyanalysis. Clin Infect Dis.2020 Jan 2;70(2):181-190. doi: 10.1093/cid/ciz177.

9. Widge AT, Rouphael NG, Jackson LA, et al.Durability of Responses after COVID-19 mRNA-1273 Vaccination. NEJM. 2020 Dec3:NEJMc2032195. doi:10.1056/NEJMc2032195.

10. Danziger-Isakov L, Kumar D. Vaccination of solid organ transplant candidates and recipients: Guidelines from the Americansociety of transplantation infectious diseases community of practice. ClinTransplant. 2019 Sep;33(9):e13563. doi:10.1111/ctr.13563.

11. Bolke E, Matuschek C, Fischer JC. Loss of Anti-COVID-19 Antibodies in Mild Covid-19. N Engl J Med 2020;383:1694-5.

12. Terpos E, Mentis A, Dimopoulos MA. Loss of Anti-COVID-19 Antibodies in Mild Covid-19. N Engl J Med 2020;383:1695.

13. Tillett RL, Sevinsky JR, Hartley PD, et al.Genomic evidence for reinfection with COVID-19: a case study. The Lancet Infectious Diseases. doi:10.2139/ssrn.3680955.

14. Caillard S,Chavarot N, Francois H, et al. Is COVID-19 infection more severe in kidney transplant recipients?. Am JTransplant. 2020. doi: https://doi.org/10.1111/ajt.16424.