ABSTRACT
Patients with symptomatic monoclonal gammopathies have impaired humoral responses to COVID-19 vaccination. Their ability to recognize SARS-CoV-2 Omicron variants is of concern. We compared the response to BNT162b2 mRNA vaccinations of patients with multiple myeloma (MM, n = 60) or Waldenstrom's macroglobulinemia (WM, n = 20) with healthy vaccine recipients (n = 37). Patient cohorts on active therapy affecting B cell development had impaired binding and neutralizing antibody (NAb) response rate and magnitude, including several patients lacking responses, even after a 3rd vaccine dose, whereas non-B cell depleting therapies had a lesser effect. In contrast, MM and WM cohorts off-therapy showed increased NAb with a broad response range. ELISA Spike-Receptor Binding Domain (RBD) Ab titers in healthy vaccine recipients and patient cohorts were good predictors of the ability to neutralize not only the original WA1 but also the most divergent Omicron variants BA.4/5. Compared to WA1, significantly lower NAb responses to BA.4/5 were found in all patient cohorts on-therapy. In contrast, the MM and WM cohorts off-therapy showed a higher probability to neutralize BA.4/5 after the 3rd vaccination. Overall, the boost in NAb after the 3rd dose suggests that repeat vaccination of MM and WM patients is beneficial even under active therapy.
ABSTRACT
Immunocompromised individuals including patients with hematological malignancies constitute a population at high risk of developing severe disease upon SARS-CoV-2 infection. Protection afforded by vaccination is frequently low and the biology leading to altered vaccine efficacy is not fully understood. A patient cohort who had received bone marrow transplantation or CAR-T cells was studied following a 2-dose BNT162b2 mRNA vaccination and compared to healthy vaccine recipients. Anti-Spike antibody and systemic innate responses were compared in the two vaccine cohorts. The patients had significantly lower SARS-CoV-2 Spike antibodies to the Wuhan strain, with proportional lower cross-recognition of Beta, Delta, and Omicron Spike-RBD proteins. Both cohorts neutralized the wildtype WA1 and Delta but not Omicron. Vaccination elicited an innate cytokine signature featuring IFN-γ, IL-15 and IP-10/CXCL10, but most patients showed a diminished systemic cytokine response. In patients who failed to develop antibodies, the innate systemic response was dominated by IL-8 and MIP-1α with significant attenuation in the IFN-γ, IL-15 and IP-10/CXCL10 signature response. Changes in IFN-γ and IP-10/CXCL10 at priming vaccination and IFN-γ, IL-15, IL-7 and IL-10 upon booster vaccination correlated with the Spike antibody magnitude and were predictive of successful antibody development. Overall, the patients showed heterogeneous adaptive and innate responses with lower humoral and reduced innate cytokine responses to vaccination compared to naïve vaccine recipients. The pattern of responses described offer novel prognostic approaches for potentiating the effectiveness of COVID-19 vaccination in transplant patients with hematological malignancies.
Subject(s)
COVID-19 , Hematologic Neoplasms , Viral Vaccines , Antibodies, Viral , BNT162 Vaccine , COVID-19/prevention & control , COVID-19 Vaccines , Chemokine CXCL10 , Cytokines , Hematologic Neoplasms/therapy , Humans , Interleukin-15 , RNA, Messenger , SARS-CoV-2ABSTRACT
Immunocompromised individuals including patients with hematological malignancies constitute a population at high risk of developing severe disease upon SARS-CoV-2 infection. Protection afforded by vaccination is frequently low and the biology leading to altered vaccine efficacy is not fully understood. A patient cohort who had received bone marrow transplantation or CAR-T cells was studied following a 2-dose BNT162b2 mRNA vaccination and compared to healthy vaccine recipients. Anti-Spike antibody and systemic innate responses were compared in the two vaccine cohorts. The patients had significantly lower SARS-CoV-2 Spike antibodies to the Wuhan strain, with proportional lower cross-recognition of Beta, Delta, and Omicron Spike-RBD proteins. Both cohorts neutralized the wildtype WA1 and Delta but not Omicron. Vaccination elicited an innate cytokine signature featuring IFN-γ, IL-15 and IP-10/CXCL10, but most patients showed a diminished systemic cytokine response. In patients who failed to develop antibodies, the innate systemic response was dominated by IL-8 and MIP-1α with significant attenuation in the IFN-γ, IL-15 and IP-10/CXCL10 signature response. Changes in IFN-γ and IP-10/CXCL10 at priming vaccination and IFN-γ, IL-15, IL-7 and IL-10 upon booster vaccination correlated with the Spike antibody magnitude and were predictive of successful antibody development. Overall, the patients showed heterogeneous adaptive and innate responses with lower humoral and reduced innate cytokine responses to vaccination compared to naïve vaccine recipients. The pattern of responses described offer novel prognostic approaches for potentiating the effectiveness of COVID-19 vaccination in transplant patients with hematological malignancies.
ABSTRACT
The speed of development, versatility and efficacy of mRNA-based vaccines have been amply demonstrated in the case of SARS-CoV-2. DNA vaccines represent an important alternative since they induce both humoral and cellular immune responses in animal models and in human trials. We tested the immunogenicity and protective efficacy of DNA-based vaccine regimens expressing different prefusion-stabilized Wuhan-Hu-1 SARS-CoV-2 Spike antigens upon intramuscular injection followed by electroporation in rhesus macaques. Different Spike DNA vaccine regimens induced antibodies that potently neutralized SARS-CoV-2 in vitro and elicited robust T cell responses. The antibodies recognized and potently neutralized a panel of different Spike variants including Alpha, Delta, Epsilon, Eta and A.23.1, but to a lesser extent Beta and Gamma. The DNA-only vaccine regimens were compared to a regimen that included co-immunization of Spike DNA and protein in the same anatomical site, the latter of which showed significant higher antibody responses. All vaccine regimens led to control of SARS-CoV-2 intranasal/intratracheal challenge and absence of virus dissemination to the lower respiratory tract. Vaccine-induced binding and neutralizing antibody titers and antibody-dependent cellular phagocytosis inversely correlated with transient virus levels in the nasal mucosa. Importantly, the Spike DNA+Protein co-immunization regimen induced the highest binding and neutralizing antibodies and showed the strongest control against SARS-CoV-2 challenge in rhesus macaques.