A Fourth Dose of COVID-19 Vaccine Does Not Induce Neutralization of the Omicron Variant Among Solid Organ Transplant Recipients With Suboptimal Vaccine Response

Abstract

Background. Humoral responses to coronavirus disease 2019 (COVID-19) vaccines are attenuated in solid organ transplant recipients (SOTRs), necessitating additional booster vaccinations. The Omicron variant demonstrates substantial immune evasion, and it is unknown whether additional vaccine doses increase neutralizing capacity versus this variant of concern (VOC) among SOTRs. Methods. Within an observational cohort, 25 SOTRs with low seroresponse underwent anti–severe acute respiratory syndrome coronavirus 2 spike and receptor-binding domain immunoglobulin (Ig)G testing using a commercially available multiplex ELISA before and after a fourth COVID-19 vaccine dose (D4). Surrogate neutralization (percent angiotensin-converting enzyme 2 inhibition [%ACE2i], range 0%–100% with >20% correlating with live virus neutralization) was measured against full-length spike proteins of the vaccine strain and 5 VOCs including Delta and Omicron. Changes in IgG level and %ACE2i were compared using the paired Wilcoxon signed-rank test. Results. Anti–receptor-binding domain and anti-spike seropositivity increased post-D4 from 56% to 84% and 68% to 88%, respectively. Median (interquartile range) anti-spike antibody significantly increased post-D4 from 42.3 (4.9–134.2) to 228.9 (1115.4–655.8) World Health Organization binding antibody units. %ACE2i (median [interquartile range]) also significantly increased against the vaccine strain (5.8% [0%–16.8%] to 20.6% [5.8%–45.9%]) and the Delta variant (9.1% [4.9%–12.8%] to 17.1% [10.3%–31.7%]), yet neutralization versus Omicron was poor, did not increase post-D4 (4.1% [0%–6.9%] to 0.5% [0%–5.7%]), and was significantly lower than boosted healthy controls. Conclusions. Although a fourth vaccine dose increases anti-spike IgG and neutralizing capacity against many VOCs, some SOTRs may remain at high risk for Omicron infection despite boosting. Thus, additional protective interventions or alternative vaccination strategies should be urgently explored.

Update on COVID-19 Therapeutics for Solid Organ Transplant Recipients, Including the Omicron Surge

“…This is particularly important for those who do not mount a robust response to COVID vaccines, given the fact that neutralization of the Omicron variant requires very high levels of antibodies, which may not be routinely achievable even with a fourth dose of mRNA vaccine in transplant recipients. 105 Other recent options for early treatment include 2 oral drugs, nirmatrelvir/ritonavir and molnupiravir (although nirmatrelvir/ritonavir has potentially severe drug-drug interactions), and a 3-d outpatient remdesivir protocol. Convalescent plasma is undergoing a resurgence of interest following recent studies on the early use of high-titer plasma that showed benefit.…”

Humoral Responses in the Omicron Era following Three-Dose SARS-CoV-2 Vaccine Series in Kidney Transplant Recipients

“…Concerningly, initial studies suggest that the ‘value-add’ of a fourth vaccine dose may be limited in those with a poor response to a three-dose vaccine series (41, 42). Among SOTRs with a weak serological response to prior vaccine doses, elevated titres of binding and neutralizing antibodies to many variants of concern were noted following a fourth dose; however, neutralization against Omicron was largely unchanged (43). In a KTR cohort, only 10% of previous non-responders after three doses achieved an adequate response following a fourth dose (44).…”

Efficacy and longevity of immune response to 3rd COVID-19 vaccine and effectiveness of a 4th dose in severely immunocompromised patients with cancer

“…A study from Israel demonstrated enhanced Omicron neutralization after a 4 th dose of COVID-19 mRNA vaccine in healthy health-care workers [37]. However a study of 25 patients with solid organ transplant recipients showed that the 4 th dose was not effective in inducing Omicron neutralization [38]. Such a study has not been published yet for patients with cancer, making this an unmet need.…”