Neutralization breadth of SARS-CoV-2 viral variants following primary series and booster SARS-CoV-2 vaccines in patients with cancer

Abstract

Patients with cancer are more likely to have impaired immune responses to SARS-CoV-2 vaccines. We study the breadth of responses against SARS-CoV-2 variants after primary vaccination in 178 patients with a variety of tumor types and after booster doses in a subset. Neutralization of alpha, beta, gamma, and delta SARS-CoV-2 variants is impaired relative to wildtype, regardless of vaccine type. Regardless of viral variant, mRNA1273 is the most immunogenic, followed by BNT162b2, and then Ad26.COV2.S. Neutralization of more variants (breadth) is associated with a greater magnitude of wildtype neutralization, and increases with time since vaccination; advancing age associates with a lower breadth. The concentrations of anti-spike protein antibody are a good surrogate for breadth (positive predictive value of =90% at >1,000 U/mL). Booster SARS-CoV-2 vaccines confer enhanced breadth. These data suggest that achieving a high antibody titer is desirable to achieve broad neutralization; a single booster dose with the current vaccines increases the breadth of responses against variants.

Keywords: Ad26.COV2.S; BNT162b2; SARS-CoV-2; booster dose; breadth; cancer; mRNA1273; neutralization; variants.

Graphical abstract

Figure 1

Neutralization of SARS-CoV-2 variants after vaccination with mRNA1273 (n = 58), BNT162b2 (n = 60), or Ad26.COV2.S (n = 60) in patients with cancer The y axis shows pseudovirus neutralization titer 50 (pNT50, defined as the titer at which the serum achieves 50% neutralization of SARS-CoV-2 wildtype pseudovirus entry into ACE2-expressing 293T cells).^. Briefly, lentiviral particles encoding both luciferase and ZsGreen reporter genes were pseudotyped with the SARS-CoV-2 spike protein from the strain indicated (see Table S1 for sequences) and produced in 293T cells, titered using ZsGreen expression by flow cytometry and used in an automated neutralization assay with 50–250 infectious units of pseudovirus co-incubated with 3-fold serial dilutions of serum for 1 h. Neutralization was determined on 293T-ACE2 cells. A horizontal dotted line is shown at a pNT50 titer of 12, which is the lower limit of detection of this assay; a pNT50 titer of 20 corresponds with the clinical threshold for positivity defined previously (Garcia-Beltran et al., 2021a). The geometric mean titer, proportion positive (at a threshold of 1:12). Statistical comparison of neutralization titers against each strain between recipients of different vaccines is details in Table S2 and denoted by a ^∗ on the graph where p value are adjusted for covariates previously shown to be associated with wildtype virus neutralization namely age, chemotherapy, immunotherapy, timing after vaccination, and cancer type. Comparison of neutralization titers for recipients of each vaccine type, against different strains is shown as the fold change in neutralization, and corresponding p value (based on a Dunnet's test conducted in GraphPad Prism v9.0). Horizontal lines denote geometric mean titers, whiskers extend to 2.5th and 97.5th centiles to encompass the 95% CI.

Figure 2

Effect of booster doses on neutralization of SARS-CoV-2 viral variants in patients with cancer (n = 13) The color of each dot indicates the initial vaccine series and additional vaccine as indicated in legend. The geometric mean titer (GMT) and proportion above the lower limit of detection (lower limit of detection = 12) is shown.