(Version 1.0; last updated October 27, 2020)

Input from Drs. Jeff Auletta, Roy Chemaly, Fareed Khawaja, Genovefa Papanicolaou, Josh Hill, Julie Kanter, Alpana Waghmare, Adrian Wiestner, John Wingard

What SARS-CoV-2 vaccines are approved for use in immunocompromised patients?

Currently, no SARS-CoV-2 vaccine is FDA-approved for administration and distribution. A list of vaccine candidates with published results from phase 1-3 clinical trials is found here.¹ Despite several vaccine candidates being in phase 2/3 clinical trials, no current clinical trial of a COVID-19 vaccine has enrolled immunocompromised patients. Thus, the efficacy and safety of a SARS-CoV-2 vaccine has not been established in the different immunocompromised patient populations.

What are mechanisms of action for the leading candidate SARS-CoV-2 vaccines?

Leading SARS-CoV-2 vaccine candidates use either conventional or novel mechanisms of action to elicit an immune response in patients. Conventional methods include attenuated inactivated (killed) virus² and recombinant viral protein³ vaccines to develop immunity. Novel approaches include replication-deficient, adenovirus vector-based vaccines that contains the SARS-CoV-2 spike protein^4,5 and mRNA-based vaccines that encode for a SARS-CoV-2 spike protein.^6,7 Based on phase 1/2 studies, candidate SARS-CoV-2 vaccines elicited both humoral and cellular immune responses. All except one of the vaccine candidates being tested require 2 separate inoculations.

Why might some hematology patients not respond to vaccines?

In order to generate optimal protective immunity following vaccination, intact host immunity is needed, particularly with respect to antigen presentation, B and T cell activation, and plasma B cell antibody generation. Therefore, hosts lacking functional adaptive immune cells may be unable to generate a fully protective immune response to a SARS-CoV-2 vaccine approved for use in the general population.

The following immunocompromised patient populations could have attenuated or absent response to SARS-CoV-2 vaccines:

1. Primary and secondary immunodeficiencies involving adaptive immunity
2. Splenectomy or functional asplenia [e.g., sickle cell disease]
3. B cell directed therapies [e.g., blocking monoclonal antibodies against CD20 or CD22, bispecific agents like blinatumomab, CD19 or CD22-directed CAR-T cell therapies, BTK inhibitors]
4. T cell directed therapies [e.g., calcineurin inhibitors, antithymocyte globulin, alemtuzumab]
5. Many chemotherapy regimens
6. High-dose corticosteroids (μ20 mg per dose or >2 mg/kg/day daily prednisone or equivalent)
7. Hematopoietic cell transplantation (HCT), especially within the first 3-6 months after autologous HCT and often longer after allogeneic HCT
8. Underlying aberrant immunity [e.g., graft-vs.-host disease (GVHD), graft rejection, absent or incomplete immune reconstitution, neutropenia ANC<500/μL, lymphopenia ALC<200/μL]

What is known about the safety and efficacy of protein-based or killed (inactivated virus) vaccines in immunocompromised patients?

Vaccine safety encompasses acute and long-term side effects associated with a vaccine. Based on experience with other recombinant protein-based and inactivated (killed) virus-based vaccines, no major side effects or unique side effects have been reported in immunocompromised patients.⁸ Common acute side effects associated with candidate SARS-CoV-2 vaccines reported to date include low-grade fever, myalgias, headache, nausea, fatigue and soreness/redness at the injection site. These acute side effects were more pronounced after the booster dose (2^nd vaccine dose) in some of the trials. Long-term side effects have not been defined for SARS-CoV-2 vaccines and will be available once phase 3 trials have completed long term follow up in healthy volunteers. Initial data on safety will be available for at least two months from vaccine administration based on Emergency Use Authorization (EUA) minimum standards. A national monitoring system exists for reporting vaccine-related adverse events.

The efficacy of protein-based or inactivated (killed) SARS-CoV-2 vaccines in immunocompromised patients has yet to be studied. Prior experience with inactivated or killed virus vaccines have demonstrated some efficacy in immunocompromised patients, leading some societies to recommend vaccination of this population.⁹ Vaccine responses are influenced by the underlying disease and the type and timing of recent therapy. The adjuvanted recombinant (protein-based) zoster vaccine was safe and elicited robust humoral and cellular immune responses across patients with hematologic malignancies when administered during or up to 6 months after immunosuppressive therapy. However, response rates in patients with CLL or non-Hodgkin lymphomas, many likely treated with anti-CD20 containing regimens, were lower than in the rest of the hematologic malignancies.¹⁰

Flu vaccines using killed virus are safe and can elicit humoral immune responses in immunocompromised patients but response rates appear to be highly variable, reported between 15-63% of CLL patients not actively treated, and in 7-26% in patients on BTK inhibitor (ibrutinib) therapy.

The immune responses to varicella zoster is a memory response, as the vast majority of people have formed antibodies against varicella zoster virus in childhood. Similarly, response to influenza is, at least in part, a memory response. In contrast, response to SARS-CoV-2 will require a de novo immune response and much less is known about how well immunocompromised patients will be able to generate such a response.

Potential considerations for testing prior to administration of SARS-CoV-2 vaccine in an immunocompromised patient include: CBC with differential, peripheral blood B and T cell immunophenotype, quantitative immunoglobulins (IgG, IgM, IgA), tetanus and pneumococcal titers, to determine if a patient is likely to mount a protective immune response. The impact of these parameters on responses to SARS-CoV-2 vaccines is unknown.

What is known about the safety and efficacy of attenuated live vaccines in immunocompromised patients?

Live attenuated vaccines carry the risk of converting to pathogenic strains with particular risk in immunocompromised patients. It is unclear if a live attenuated SARS-COV-2 vaccine will have the same major risk, but due to the theoretical concerns, a live vaccine should be avoided in immunocompromised patients. Another potential risk from live-attenuated vaccines in general is the possible transmission of the virus to close contacts of the vaccinees. The only live SARS-CoV-2 vaccines are in production in India and Turkey.

Although there are no data for mRNA/DNA and using other viruses to deliver vaccines, what are the theoretical considerations in immunocompromised patients?

mRNA/DNA-based and virus vector-based (usually adenovirus) vaccines have been previously proposed with some application for cancer treatment. Theoretical concerns for their use include a hyper-inflammatory response, which was described in some animal models who received adenovirus vector vaccines.⁹ This effect has not been demonstrated in humans. Another concern is the development of autoimmune syndromes related to the increased type I interferon response elicited by an mRNA/DNA vaccine.¹¹

Given patients with chronic lymphocytic leukemia, lymphoma or myelodysplasia may be prone to other immune-mediated complications, there is some concern that generating anti-SARS-CoV-2 antibodies in these patients could lead to immune enhancement and a systemic inflammatory response akin to what is seen with multisystem inflammatory syndrome in children (MIS-C).

Across RNA-based vaccine candidates, observed side effects reported to date have been similar to those experienced with the seasonal influenza vaccination, but may be more common given the two-dose schedule for most SARS-CoV-2 mRNA vaccines:

• Pain at the injection site (up to 60%)
• Fever (up to 50%)
• Headache (up to 42%)
• Fatigue (up to 28%)
• Joint pain (up to 24%)

Are any trials of SARS-CoV-2 vaccines being done in immunocompromised populations?

Currently, no SARS-CoV-2 vaccine trial is enrolling patients receiving immunosuppressive therapy. Most trials require patients to be off immunosuppression for a certain period of time to be eligible. This may not be feasible in patients who are receiving therapy for solid organ transplant, graft versus host disease or hematologic malignancy. It is unclear how the different SARS-CoV-2 vaccine candidates will specifically affect different forms of immune abnormalities. Given the diversity of various immunocompromised patient populations, it is possible that candidate SARS-CoV-2 vaccines may differ in their efficacy and safety for these patients.

If immunocompromised patients were not included in the vaccine trials and are less likely to respond to a SARS-CoV-2 vaccine, should they still receive it? What is the timing in relation to chemotherapy, transplant, antibody therapy, splenectomy etc. Should higher vaccine doses or multiple vaccine types be used?

The risks and benefits for immunocompromised patients receiving a SARS-CoV-2 vaccine should be weighed on a case-by-case basis, with consideration of the incidence of infection in the community. This will depend on the approved vaccine formulation available, level of immunosuppression the patient has received, and the underlying reason for immunosuppressive therapy (e.g., cancer treatment, transplantation). If plans to proceed with the SARS-CoV-2 vaccine are made, vaccination is recommended at least 2-4 weeks prior to the planned immunosuppressive therapy, transplant or splenectomy. If the patient is receiving or has received immunosuppressive therapy, consider vaccination 6 months after the patient has been taken off therapy to increase the likelihood of developing immunity (see potential laboratory testing). After HCT, inactivated vaccines have generally shown low incremental risks and have not caused or worsened GVHD; thus, inactivated vaccines are generally started after 3-6 months. If SARS-CoV-2 infection rates are low in a community and a given patient is expected to have improved immune status in upcoming months, clinical judgment is appropriate when weighing the desire for protection as early as possible versus delaying vaccination to give the best chance for response. These recommendations may change, based on the results of the approved vaccine trials. Most experts recommend vaccination as long as the vaccine is safe for use, even if the expected protection rate is lower than the general population.

Importantly, vaccination does not change required precautionary behaviors such as masking, social distancing, and frequent hand hygiene. Influenza vaccination should also be administered to immunocompromised patients to reduce the burden of influenza infection and possible dual infection with SARS-CoV-2. Finally, all healthcare workers and household contacts should receive a SARS-CoV-2 vaccine to help protect immunocompromised patients, similar to the recommendations for influenza.

Whether or not an immunocompromised patient is known to have been infected with SARS-CoV-2 should not affect the decision of whether to vaccinate. Although some immunity is anticipated from experiencing a COVID-19 clinical infection, this immunity may be insufficient or wane,^12,13 especially in immunocompromised hosts. However, increased side effects could be seen with vaccination, similar to what is observed with the second dose in a two-dose vaccine series.

Until more is known, different SARS-CoV-2 vaccines should not be given to the same patient. Although measuring titers may eventually be helpful to assess response, more information is needed. Giving more inoculations or higher doses of an approved SARS-CoV-2 vaccine is not recommended at this time.

References

1. Goodman JL, Grabenstein JD, Braun MM. Answering Key Questions About COVID-19 Vaccines. JAMA 2020.
2. Xia S, Duan K, Zhang Y, et al. Effect of an Inactivated Vaccine Against SARS-CoV-2 on Safety and Immunogenicity Outcomes: Interim Analysis of 2 Randomized Clinical Trials. JAMA 2020;324:951-60.
3. Keech C, Albert G, Cho I, et al. Phase 1-2 Trial of a SARS-CoV-2 Recombinant Spike Protein Nanoparticle Vaccine. N Engl J Med 2020.
4. Folegatti PM, Ewer KJ, Aley PK, et al. Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial. Lancet 2020;396:467-78.
5. 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;396:479-88.
6. Anderson EJ, Rouphael NG, Widge AT, et al. Safety and Immunogenicity of SARS-CoV-2 mRNA-1273 Vaccine in Older Adults. N Engl J Med 2020.
7. Walsh EE, Frenck RW, Jr., Falsey AR, et al. Safety and Immunogenicity of Two RNA-Based Covid-19 Vaccine Candidates. N Engl J Med 2020.
8. Rubin LG, Levin MJ, Ljungman P, et al. 2013 IDSA clinical practice guideline for vaccination of the immunocompromised host. Clin Infect Dis 2014;58:e44-100.
9. Bos R, Rutten L, van der Lubbe JEM, et al. Ad26 vector-based COVID-19 vaccine encoding a prefusion-stabilized SARS-CoV-2 Spike immunogen induces potent humoral and cellular immune responses. NPJ Vaccines 2020;5:91.
10. Dagnew AF, Ilhan O, Lee WS, et al. Immunogenicity and safety of the adjuvanted recombinant zoster vaccine in adults with haematological malignancies: a phase 3, randomised, clinical trial and post-hoc efficacy analysis. Lancet Infect Dis 2019;19:988-1000.
11. Pardi N, Hogan MJ, Porter FW, Weissman D. mRNA vaccines - a new era in vaccinology. Nat Rev Drug Discov 2018;17:261-79.
12. Bolke E, Matuschek C, Fischer JC. Loss of Anti-SARS-CoV-2 Antibodies in Mild Covid-19. N Engl J Med 2020;383:1694-5.
13. Terpos E, Mentis A, Dimopoulos MA. Loss of Anti-SARS-CoV-2 Antibodies in Mild Covid-19. N Engl J Med 2020;383:1695.