Humoral immune responses against SARS‐CoV‐2 in transplantation: Actionable biomarker or misplaced trust?

Measures of vaccine‐specific antibodies to SARS‐CoV‐2, as discussed by Werbel and Segev (Page 1316), may ignore responses to contemporaneous variants of concern and relevant cellular immune responses, thereby failing to provide the insights required to optimize clinical care.


Humoral immune responses against SARS-CoV-2 in transplantation: Actionable biomarker or misplaced trust?
In addition to a remarkable ability to spread and mutate, severe acute Boosting improves antibody quality in immune competent hosts via enhanced affinity maturation, providing antibodies that recognize a broader array of variants. 14 In immunocompromised hosts, incomplete responses to vaccination could produce greater humoral immune responses in the absence of enhanced affinity maturation. Such lower affinity antibodies may neutralize wildtype SARS-CoV-2 found in vaccines, but with lesser cross-reactivity to additional variants of concern (e.g., Omicron). Incomplete affinity maturation in SOT could relate to impaired T cell help, disrupted germinal center activity, or altered antigen presentation. 15 Thus, in the absence of a complete understanding the affin-

ity and breadth of neutralization of the antibody response, S-specific titers may not adequately characterize protection against SARS-CoV-2 variants.
Clinical laboratories are overwhelmed with requests for diagnostic assays during COVID. In a viewpoint paper by Werbel and Segev, measurement of antibody levels is advocated as an adjunct to clinical management. 16 They recommend quantitative FDA emergency use authorized anti-S1/RBD assays after full vaccination to assess antibody responses. As they note, there are few data supporting Mab use in vaccinated seronegative SOT recipients (or poor responders). The key question is whether antibody levels in SOT recipients are actionable biomarkers or simply an available assay, reassuring to the physician or patient but failing to reflect immune function?
AJT EDITORIAL With the appearance of Omicron BA.2, emerging antiviral therapies must be provided to those least likely to mount an effective immune response. Based on which tests? And is this the best use of a limited resource? In the immunodominant spike (S) protein, 5106 different amino acid replacements or substitutions have been identified as well as multiple deletions. 17 As variants emerged, natural antibodies (from prior infection), therapeutic monoclonal antibodies (targeting prior strains), and some vaccine-elicited antibodies have become less effective in preventing disease progression. 18 More than 85% of tested neutralizing antibodies are escaped by Omicron 19 ; nearly all are escaped by Omicron sublineage BA.2. 20 Thus, routine assays for SARS-CoV-2 antibody levels might erroneously suggest viral protection when none exists to emerging variants.
Antibody levels provide an imperfect foundation for decisions regarding disease prevention or treatment. Assays of neutralizing antibodies detect vaccine-specific antibodies but may not measure antibodies to contemporaneous variants of concern. Furthermore, maintenance of antibody levels sufficient to maintain lifelong protection against viral transmission is an unrealistic goal. Instead, we need to understand the precise functional correlates of immunity responsible for disease control. Emerging multiplexed antibody assays will interrogate antibody binding across variants and may provide information regarding the efficacy of vaccine-induced or monoclonal transmission blocking activity. As further vaccine variants emerge, new pan-variant vaccines will be required. Identification of the key correlates of immunity will provide SOT patients and clinicians the insights required to optimize clinical care in this and future pandemics.

D I SCLOS U R E
The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.