key: cord-0683693-n2pdhhg7
authors: Ison, Michael G.; Blumberg, Emily; Halasa, Natasha; Kaul, Dan; Theodoropoulos, Nicole M.; Wolfe, Cameron R.
title: Antibodies, boosters, and optimizing SARS‐CoV‐2 vaccines for transplantation: A call for more research
date: 2021-07-26
journal: Am J Transplant
DOI: 10.1111/ajt.16758
sha: a57dc31022091d03cbb8e80461ba40206c77dfc2
doc_id: 683693
cord_uid: n2pdhhg7

Despite emerging data suggesting reduced antibody responses among solid organ transplant recipients following SARS‐CoV‐2 vaccine, critical unanswered questions remain. The clinical implications of the reduced humoral response need to be assessed through prospective studies. Studies are likewise needed to inform which vaccine dosing strategies result in improved immunity and if such approaches maximize protection against severe infection in the vulnerable transplant population.

As additional information has emerged on the clinical and immunologic efficacy of SARS-CoV-2 vaccine responses in immunocompromised patients, it has become clear that further data are needed to inform the best clinical practices. While some have advocated for wider use of routine serologic assessment and booster doses based on existing data, questions remain about the utility and safety of such approaches.

As outlined by a recent advisory from the US Food and Drug Administration (FDA), 1 current emergency use authorized serologic assays were developed as a diagnostic tool and not to assess humoral vaccine responses. Assays differ based on target, assessment of neutralizing antibodies, and ability to provide quantitative titers and none have had protective thresholds defined. Such assays are only a surrogate marker for immunity, as they do not measure the full spectrum of comprehensive and specific immunologic responses to the vaccine. As a result, patients and providers may be misled to think a positive result is definitive proof of protection or a negative result as a vaccine failure-both of which can be dangerous. For example, cellular immune responses are not routinely measured but have been documented even among seronegative vaccinated patients; these responses may provide protection against severe disease. 2 Further, solid organ transplant (SOT) recipients who have positive results frequently have titers that are significantly lower compared to healthy vaccinated patients and which may be less effective against novel variants. 3 Lastly, since seroprotective titers have not been established, interpretation of the results is extremely challenging. A recently completed study that looked at the response to a booster (third) dose of an mRNA based, for all transplant patients, did not use serology to inform the decision to give the third dose and yet benefit was seen in all seropositive and many seronegative patients. 4 More data are needed before post-vaccine serologic testing of SOT recipients can be recommended as part of standard of care. Further, the data from this French study suggest that having post-second dose data is likely not needed as it is unlikely to affect further management.

The currently authorized vaccines were assessed based on prevention of clinical COVID-19 and we should be looking carefully at both the risk and severity of breakthrough infection in SOT recipients. From available data, immunocompetent vaccinated individuals rarely developed breakthrough infections and these infections were infrequently severe and/or fatal. 5 While rates of breakthrough infection after completing vaccine are higher in SOT recipients than in the general population, they remain rare (0.65%) and are, like breakthrough infections in immunocompetent, rarely severe. 6, 7 While the number of patients remain low, there were no breakthrough infections in 131 patients who received a third dose, despite the fact that 38% remain seronegative after three doses. 4, 8 Without evidence of poor clinical outcomes in vaccinated SOT patients, it is unclear if a rush to "improve" vaccine responses is necessary. In fact, available data indicate a need for a more thoughtful scientific approach.

Early data on a third dose of vaccine has recently been published from two groups. 4, 8 While there has been a lot of interest in these studies, they must be interpreted cautiously. The American study is The American case series also raises concerns about safety as one heart transplant recipient (3.3% of studied patients) developed a biopsy-proven, antibody-mediated rejection 7 days after her third dose of vaccine; no specific details, including immunosuppression adjustments to optimize vaccine responses, are provided in the paper. 8 No patients in the French series experienced rejection. 4 By comparison, one patient (0.13%) developed acute rejection from a larger case series of 741 patients from a study of the safety of two doses of SARS-CoV-2 vaccine in SOT recipients. 9 If true, this could represent up to a sixfold higher rate of rejection after a third dose, and potential unanticipated risk. Since the two studies included few heart recipients and there are emerging data that the mRNA vaccines can induce myocarditis, further data are likely needed, particularly in this unique population. 4, 8, 10 Taken together, the limited data do not yet support routine test- Collecting such data will require more than single site reports but instead data collaboration across a wide range of centers, transplant As there is significant interest from patients in booster dosing, we would encourage providers to discuss that the risks and benefits are uncertain; available data suggest that the booster does not improve responses in many patients and that, in the absence of data, patients interested in booster doses should be discouraged from getting additional doses outside of a controlled research setting. 

Data sharing is not applicable to this article as no new data were created or analyzed in this study. 

ng-not-curre ntly-recom mende d-asses s-immun ity-after -covid -19-vacci natio n-fda-safety

Cellular immunity predominates over humoral immunity after the first dose of COVID-19 vaccines in solid organ transplant recipients

Antibody response to 2-dose SARS-CoV-2 mRNA vaccine series in solid organ transplant recipients

Three doses of an mRNA Covid-19 vaccine in solid-organ transplant recipients

COVID-19 vaccine breakthrough infections reported to CDC -United States

COVID-19 infection in solid organ transplant recipients after SARS-CoV-2 vaccination

Effectiveness of SARS-CoV-2 vaccination in fully-vaccinated solid organ transplant recipients

Safety and immunogenicity of a third dose of SARS-CoV-2 vaccine in solid organ transplant recipients: a case series

Safety and reactogenicity of 2 doses of SARS-CoV-2 vaccination in solid organ transplant recipients. Transplantation

Centers for Disease Control and Prevention Myocarditis and Pericarditis Following mRNA COVID-19 Vaccination

Alternative strategies of posttransplant influenza vaccination in adult solid organ transplant recipients

A 5-year prospective multicenter evaluation of influenza infection in transplant recipients

How to cite this article: Ison MG

Antibodies, boosters, and optimizing SARS-CoV-2 vaccines for transplantation: A call for more research