The third dose of mRNA SARS-CoV-2 vaccines enhances the spike-specific antibody and memory B cell response in myelofibrosis patients

Abstract

Vaccination against SARS-CoV-2 using mRNA-based vaccines has been highly recommended for fragile subjects, including myelofibrosis patients (MF). Available data on the immune responsiveness of MF patients to mRNA SARS-CoV-2 vaccination, and the impact of the therapy with the JAK inhibitor ruxolitinib, are still fragmented. Here, we profile the spike-specific IgG and memory B-cell response in MF patients, treated or not with ruxolitinib, after the second and the third dose of SARS-CoV-2 BNT162b2 (BioNTech) and mRNA-1273 (Moderna) vaccines. Plasma and peripheral blood mononuclear cells samples were collected before vaccination, post the second and the third doses and tested for spike-specific antibodies, ACE2/RBD antibody inhibition binding activity and spike-specific B cells. The third vaccine dose significantly increased the spike-specific IgG titers in both ruxolitinib-treated and untreated patients, and strongly enhanced the percentage of subjects with antibodies capable of in vitro blocking ACE2/RBD interaction, from 50% up to 80%. While a very low frequency of spike-specific B cells was measured in blood 7 days after the second vaccination dose, a strong and significant increase was elicited by the third dose administration, generating a B cell response similar to the one detected in healthy controls. Despite the overall positive impact of the third dose in MF patients, two patients that were under active concomitant immunosuppressive treatment at the time of vaccination, and a patient that received lymphodepleting therapies in the past, remained low responders. The third mRNA vaccine dose strongly increases the SARS-CoV-2 specific humoral and B cell responses in MF patients, promoting a reactivation of the immune response similar to the one observed in healthy controls.

Ruxolitinib treatment in myelofibrosis and polycythemia vera causes suboptimal humoral immune response following standard and booster vaccination with BNT162b2 mRNA COVID-19 vaccine

“…In particular, ruxolitinib, a widely used JAKi ( 22 – 27 ), is known to downregulate immune response with effects on B, T, dendritic, and NK cells ( 28 ) and could be the primary cause of the inferior efficacy of vaccination. Confirming this hypothesis, in patients undergoing ruxolitinib treatment, recently, an impaired response to the first ( 29 ) and second dose of vaccine ( 21 , 47 ) has been demonstrated. Antibodies elicited by vaccination are of key importance to protect subjects from the disease or, in other words, might be able to neutralize the virus ( 38 ).…”

Analysis of Antibodies Induced after SARS-CoV-2 Vaccination Using Antigen Coded Bead Array Luminex Technology

“…Therefore, booster vaccination may be useful. There have been studies that have explored changes in serum neutralizing antibodies after a third dose of CoronaVac [ 40 , 41 , 42 ] and have shown that neutralization titers (GMT) increased rapidly if a booster was administered 6–8 months after the second dose of CoronaVac, suggesting that a third vaccination could significantly induce an immune recall response in specific memory B cells. Overall, the results of other related studies and our study support the promotion of booster vaccination to reduce the rate of COVID-19 infections, hospitalizations, and mortality [ 17 , 18 , 43 ].…”

Profiling the B cell immune response elicited by vaccination against the respiratory virus SARS-CoV-2

“…The B cell response has been recently characterized also in fragile patients such as hematopoietic cell transplantation recipients, myelofibrosis patients and people living with HIV, immunized with mRNA vaccines ( 6 , 8 , 33 ). These studies have highlighted the crucial role of the third dose in increasing the frequency of spike-specific B cells, generating a response similar to the one detected in healthy controls.…”

“…Confounding factors have been recognized in race, gender, age, comorbidities and immunosuppressive drug treatments (3). For example, age and immunological disorders, which can induce physiological and premature immune senescence, respectively, as well as chronic systemic low-grade inflammation have been considered among the most impacting factors on immune responsiveness to vaccination (4)(5)(6)(7)(8).…”

“…The decrease in circulating antibodies correlated with an increase of SARS-CoV-2 infection among vaccinated subjects ( 15 , 17 ), prompting regulatory agencies to promote booster doses of vaccination order to raise the amount of circulating antibodies. The effect of the third booster dose proved particularly effective in some cohorts of fragile subjects, in whom the response to the first vaccination cycle had appeared slower and less intense ( 5 , 6 , 8 , 18 , 19 ). The booster dose also demonstrated the ability to reinvigorate the entire antibody response, also significantly increasing the levels of antibodies cross-reactive with new circulating variants of concerns, such as Delta and Omicron ( 18 ).…”