ABSTRACT
Introduction: Current SARS-CoV-2 vaccines are effective at preventing COVID-19 or limiting disease severity in healthy individuals, but effectiveness is lower among patients with cancer or immunosuppression. Vaccine effectiveness wanes with time and varies by vaccine type. Moreover, current vaccines are based on the ancestral SARS-CoV-2 spike protein sequence, and emerging viral variants evade vaccine induced immunity. Booster doses partially overcome these issues, but there are limited clinical data on the durability of protection afforded by boosters - especially against SARS-CoV-2 variants. Methods: Here we describe a mechanistic mathematical model for vaccination-induced immunity in patients with cancer and use it to predict vaccine effectiveness taking into account current and possible future viral, host and vaccine characteristics. Crucially, this allows predictions over time frames currently not reported in the clinical literature. The model incorporates the infection of lung epithelium by SARS-CoV-2, the response of innate and adaptive immune cells to infection, the production of pro-and anti-inflammatory cytokines, the activation of the coagulation cascade. The model further accounts for the interactions between the virus, immune cells and tumor cells as well as for vaccination-induced immunity and anti-cancer therapies. Results: Model predictions were validated with available clinical data. The model predicts that for healthy individuals vaccinated and boosted with mRNA-1273, BNT-162b2a, and Ad26.COV2.S, robust immunogenicity against the ancestral and delta variant extends beyond a year. Immunogenicity is enhanced following booster vaccination in patients with cancer on various anti-cancer therapies and for patients without cancer on immunosuppressive agents. However, our model predicts that more than one booster dose will be required for patients with cancer, or on immunosuppression, to maintain protective immunity against current and hypothetical future variants. SARS-CoV2 variants with enhanced binding to target cells, reduced affinity for vaccine-generated antibodies or reduced immunogenicity resulted in lower antibody levels and more severe disease compared with variants with enhanced viral replication or internalization rates. Conclusion: For patients with cancer and immunosuppressed individuals, SARS-CoV2 variants with enhanced ability to bind to target cells, altered antibody affinity or reduced immunogenicity could lead to breakthrough infections even after a single booster dose. Our mathematical model is useful for anticipating and planning future vaccinations in patients with cancer.
ABSTRACT
Background: CDK 4/6 inhibitors have transformed the landscape of breast oncology. A CDK 4/6 inhibitor in combination with endocrine therapy is recommended as 1st line therapy for patients with metastatic hormone receptor positive breast cancer. CDK 4/6 inhibitors have purported immunomodulatory effects and while effective, myelosuppression is a common adverse effect of CDK 4/6 inhibitor treatment of breast cancer. The impact of CDK 4/6 inhibitor therapy on immunogenicity of vaccines is not known. In this study, we evaluated the spike antibody response to SARS-CoV-2 vaccines among patients with breast cancer receiving endocrine therapy with or without CDK 4/6 inhibitors. Methods: In the Cancer COVID and Vaccine (CANVAX) study eligible patients included patients with breast cancer who had completed all scheduled doses of SARS-CoV-2 vaccines. Chart review was conducted to identify patients who had received endocrine therapy with or without CDK 4/6 inhibitor. We used validated assays to measure anti-SARS-CoV-2 total IgA/M/G spike antibodies and virus neutralization. We evaluated the magnitude of antibody response based on geometric mean concentrations (GMCs) as well as the % of patients with inadequate seroconversion (defined as levels <100 U/ml). Independent T-test based on log-transformed antibody values was utilized to compare the spike antibody levels and p value of ≤ 0.05 Swas considered statistically significant. Results: Between April 2021 and June 2021, 203 patients with breast cancer were enrolled. As of the cut-off date (2nd July 2021), results were available for 73 patients treated with endocrine therapy alone (N = 23), or with CDK 4/6 inhibitor-based therapy (N = 50). Most were females (98.6%), white (83.6%), and had metastatic breast cancer (68.5%). 49.3% had received BNT162b2 (Pfizer), 37% mRNA1273 (Moderna), and 13.7% Ad26.COV2.S (Johnson and Johnson/Janssen) vaccines. Overall, the mean spike antibody levels were similar between patients treated with endocrine therapy alone vs CDK 4/6 inhibitor-based therapy (GMC: 326 vs. 719 U/mL;p=0.704). Mean spike antibody levels were higher in patients with early breast cancer vs. metastatic breast cancer (GMC: 555 vs. 465 U/mL;p=0.031). However, patients who received Ad26.COV2.S had lower levels of mean spike antibody levels (GMC 47 U/ml), compared with patients treated with BNT162b2 (GMC 400 U/ml) or mRNA1273 (GMC 2203 U/mL;P<0.01 for both comparisons). Comparison of neutralization titers in 66 individuals supported the above results. 11 (15.1%) patients had low antibody titers (<100U/ml) of seroconversion and 3 received a booster vaccine, with 1 having available repeat titer results thus far demonstrating a significant improvement. Conclusions: The majority of patients receiving CDK 4/6 inhibitor have adequate antibody response to SARS-CoV-2 vaccines, particularly mRNA vaccines. However, a minority of patients may require booster vaccine to augment immunity. Monitoring spike antibody levels could be helpful to identify patients with inadequate seroconversion and guide mitigation strategies for patients with breast cancer.