Immunogenicity and Reactogenicity of SARS-CoV-2 Vaccines in Patients With Cancer: The CANVAX Cohort Study

Abstract

Purpose: The immunogenicity and reactogenicity of SARS-CoV-2 vaccines in patients with cancer are poorly understood.

Methods: We performed a prospective cohort study of adults with solid-organ or hematologic cancers to evaluate anti-SARS-CoV-2 immunoglobulin A/M/G spike antibodies, neutralization, and reactogenicity ≥ 7 days following two doses of mRNA-1273, BNT162b2, or one dose of Ad26.COV2.S. We analyzed responses by multivariate regression and included data from 1,638 healthy controls, previously reported, for comparison.

Results: Between April and July 2021, we enrolled 1,001 patients; 762 were eligible for analysis (656 had neutralization measured). mRNA-1273 was the most immunogenic (log₁₀ geometric mean concentration [GMC] 2.9, log₁₀ geometric mean neutralization titer [GMT] 2.3), followed by BNT162b2 (GMC 2.4; GMT 1.9) and Ad26.COV2.S (GMC 1.5; GMT 1.4; P < .001). The proportion of low neutralization (< 20% of convalescent titers) among Ad26.COV2.S recipients was 69.9%. Prior COVID-19 infection (in 7.1% of the cohort) was associated with higher responses (P < .001). Antibody titers and neutralization were quantitatively lower in patients with cancer than in comparable healthy controls, regardless of vaccine type (P < .001). Receipt of chemotherapy in the prior year or current steroids were associated with lower antibody levels and immune checkpoint blockade with higher neutralization. Systemic reactogenicity varied by vaccine and correlated with immune responses (P = .002 for concentration, P = .016 for neutralization). In 32 patients who received an additional vaccine dose, side effects were similar to prior doses, and 30 of 32 demonstrated increased antibody titers (GMC 1.05 before additional dose, 3.17 after dose).

Conclusion: Immune responses to SARS-CoV-2 vaccines are modestly impaired in patients with cancer. These data suggest utility of antibody testing to identify patients for whom additional vaccine doses may be effective and appropriate, although larger prospective studies are needed.

FIG 1.

Immunogenicity of mRNA-1273, BNT-162b2, and Ad26.COV2.S in CANVAX participants. (A) The quantitative SARS-CoV-2 spike IgG/A/M antibody concentration (Roche Elecsys Anti–SARS-CoV-2 assay) in U/mL of serum for 762 CVX and 418 HCs included for interpretation. Individual measures are grouped by antibody-confirmed prior infection and vaccine. Total antispike (IgA/M/G) antibody concentrations > 2,500 U/mL triggered additional manual dilution (where sample availability allowed) to yield titers up to 250,000 U/mL. An antibody cutoff index (COI) > 0.8 was defined as positive (dotted line). All assays were run blinded to clinical information. The number of donors, GMC in log₁₀ U/mL, and proportion positive are shown above each group. (B) pNT50 (defined as the titer at which the serum achieves 50% neutralization of SARS-CoV-2 wild-type pseudovirus entry into ACE2-expressing 293T cells) for 656 CVXs and 255 HCs and an additional 1,220 prepandemic controls (from Wilfredo Garcia-Beltran et al) used in assay validation.^, Briefly, lentiviral particles encoding both luciferase and ZsGreen reporter genes were pseudotyped with SARS-CoV-2 spike protein (Wuhan strain) 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 coincubated with three-fold serial dilutions of serum for 1 hour. Neutralization was determined on 293T-ACE2 cells. A horizontal dotted line is shown at a pNT50 titer of 27.6 equivalent to 20% of the convalescent titer that is predicted to be associated with 50% protection. The number of donors, GMT, proportion with titers > 20% of the absolute geometric mean titer of convalescent healthy donors (which is 138) are shown above each group. (A and B) For each group, the horizontal line denotes the GMC or GMT, and whiskers denote the 95% CI. Corresponding statistical comparisons among CANVAX participants are as shown in Table 2; comparisons between CANVAX and healthy controls are shown in the Data Supplement. CANVAX, cancer, COVID, and vaccination; CVX, CANVAX patients; GMC, geometric mean concentration; GMT, geometric mean titer; HC, healthy control; Ig, immunoglobulin; pNT50, pseudovirus neutralization titer 50.

FIG 2.

Antispike immunoglobulin A/G/M antibody concentrations (top row) and neutralization titers following mRNA-1273 (left column), BNT-162b2 (middle column), or Ad26.COV2.S (right column) according to cancer-directed therapies received in the preceding 12 months among participants without prior infection (nucelocapsid antibody-negative). Horizontal line denotes the GMC or titer and whiskers denote the 95% CI. Corresponding adjusted statistical comparisons are provided in Table 2. GMC, geometric mean concentration; GMT, geometric mean titer; ICI, immune checkpoint blockade; pNT50, pseudovirus neutralization titer 50; TT, targeted therapy.

FIG 3.

Local (left column) and systemic (right column) reactogenicity of SARS-CoV-2 vaccines and their association with antispike immunoglobulin A/G/M antibody concentrations (middle row) or neutralization titer (bottom row). (A and B) Bars are colored according to vaccine (blue mRNA-1273, red BNT162b2, and teal Ad26.COV2.S) and timing of symptoms: lower solidly shaded box indicates after first dose only, middle moderately shaded box indicates after both doses, and upper lightly shaded box indicates after second dose only. (C-F) Horizontal line denotes the geometric mean concentration or titer and whiskers denote the 95% CI. pNT50, pseudovirus neutralization titer 50.

FIG 4.

Reactogenicity and immunogenicity of additional doses of SARS-CoV-2 vaccines following completion of the primary series of vaccines (n = 32). (A and B) The frequency of local and systemic symptoms following receipt of an additional vaccine dose among 26 of 32 individuals who completed the questionnaire. (C) The antispike IgA/G/M concentration before and after receipt of a booster dose of vaccination. The color of each dot indicates the initial vaccine series and additional vaccine as indicated in the legend insert. The number of donors, GMC, and proportion positive at a threshold of > 0.8 U/mL are shown above each group. GMC, geometric mean concentration; Ig, immunoglobulin.