Neutralizing antibodies to Omicron after the fourth SARS-CoV-2 mRNA vaccine dose in immunocompromised patients highlight the need of additional boosters

Abstract

IntroductionImmunocompromised patients have been shown to have an impaired immune response to COVID-19 vaccines.MethodsHere we compared the B-cell, T-cell and neutralizing antibody response to WT and Omicron BA.2 SARS-CoV-2 virus after the fourth dose of mRNA COVID-19 vaccines in patients with hematological malignancies (HM, n=71), solid tumors (ST, n=39) and immune-rheumatological (IR, n=25) diseases. The humoral and T-cell responses to SARS-CoV-2 vaccination were analyzed by quantifying the anti-RBD antibodies, their neutralization activity and the IFN-γ released after spike specific stimulation.ResultsWe show that the T-cell response is similarly boosted by the fourth dose across the different subgroups, while the antibody response is improved only in patients not receiving B-cell targeted therapies, independent on the pathology. However, 9% of patients with anti-RBD antibodies did not have neutralizing antibodies to either virus variants, while an additional 5.7% did not have neutralizing antibodies to Omicron BA.2, making these patients particularly vulnerable to SARS-CoV-2 infection. The increment of neutralizing antibodies was very similar towards Omicron BA.2 and WT virus after the third or fourth dose of vaccine, suggesting that there is no preferential skewing towards either virus variant with the booster dose. The only limited step is the amount of antibodies that are elicited after vaccination, thus increasing the probability of developing neutralizing antibodies to both variants of virus.DiscussionThese data support the recommendation of additional booster doses in frail patients to enhance the development of a B-cell response directed against Omicron and/or to enhance the T-cell response in patients treated with anti-CD20.

Hybrid Immunity Improves the Immune Response after the Fourth COVID-19 Vaccine Dose in Individuals with Medical Conditions Predisposing to Severe COVID-19

“…Due to the significant waning of antibody levels in the months following the third dose [ 39 , 46 ] and the emergence of SARS-CoV-2 variants with a high potential of immune escape, the European Center for Disease Prevention and Control and European Medicine Agency recommended, in July 2022, the administration of the fourth dose to people above 60 years of age as well as to vulnerable persons of any age [ 47 ]. The fourth vaccine dose has been shown to elicit higher antibody levels than the third dose in immunocompromised patients [ 48 ] but lower levels than in the controls in studies with patients on immunosuppressive therapy [ 49 ] and RD [ 50 ]. Few studies have, however, reported NAbs, T cell-mediated or hybrid immunity, and the persistence of antibodies after the fourth dose in patients with CKD and RD.…”

“…One study reported increased neutralizing activity and T-cell response after the fourth dose in patients with RD. However, in only a minority of the subjects, the level of neutralization against the Omicron BA.2 strain was above baseline [ 50 ].…”

“…Our study evaluated humoral immune responses to vaccination and infection, but we did not assess cellular immunity, which is a limitation in our study. Recent data show that despite impaired B-cell responses to vaccination, specific T-cell responses are less dependent on disease or treatment characteristics [ 38 , 40 , 50 , 54 ]. The ability to attain a T-cell response depends essentially on the extent to which immunodeficiency or immunosuppressive therapy affects T cells.…”

Hybrid immunity improves the immune response after fourth Covid-19 vaccine dose in individuals with medical conditions predisposing to severe Covid-19

“…Few studies have, however, reported NAbs, T cell mediated or hybrid immunity and persistence of antibodies after fourth dose in patients with CKD and RD. One study reported increased neutralizing activity and T cell response after fourth dose in patients with RD, with only a minority displaying a level of neutralization above baseline for the Omicron BA.2 strain [49].…”

“…Due to significant waning of antibody levels in the months following the third dose [38, 44, 45] and the emergence of SARS-CoV-2 variants with a high potential of immune escape The European Center for Disease Prevention and Control and European Medicine Agency recommended in July 2022 the administration of the fourth dose to people above 60 years as well as vulnerable persons of any age [46]. Fourth vaccine dose has been shown to elicit higher antibody levels than after the third dose in immunocompromised patients [47], but lower levels than in controls after three doses in studies with patients on immunosuppressive therapy [48], RD [49] and with CKD [40, 44]. Few studies have, however, reported NAbs, T cell mediated or hybrid immunity and persistence of antibodies after fourth dose in patients with CKD and RD.…”