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Clinical Trial
. 2021 Dec;22(12):1681-1691.
doi: 10.1016/S1470-2045(21)00574-X. Epub 2021 Nov 9.

mRNA-1273 COVID-19 vaccination in patients receiving chemotherapy, immunotherapy, or chemoimmunotherapy for solid tumours: a prospective, multicentre, non-inferiority trial

Sjoukje F Oosting  1 , Astrid A M van der Veldt  2 , Corine H GeurtsvanKessel  3 , Rudolf S N Fehrmann  1 , Rob S van Binnendijk  4 , Anne-Marie C Dingemans  5 , Egbert F Smit  6 , T Jeroen N Hiltermann  7 , Gerco den Hartog  4 , Mathilda Jalving  1 , Tatjana T Westphal  8 , Arkajyoti Bhattacharya  1 , Marieke van der Heiden  9 , Guus F Rimmelzwaan  10 , Pia Kvistborg  11 , Christian U Blank  12 , Marion P G Koopmans  3 , Anke L W Huckriede  9 , Cecile A C M van Els  13 , Nynke Y Rots  4 , Debbie van Baarle  14 , John B A G Haanen  12 , Elisabeth G E de Vries  1
Affiliations
Clinical Trial

mRNA-1273 COVID-19 vaccination in patients receiving chemotherapy, immunotherapy, or chemoimmunotherapy for solid tumours: a prospective, multicentre, non-inferiority trial

Sjoukje F Oosting et al. Lancet Oncol. 2021 Dec.

Abstract

Background: Patients with cancer have an increased risk of complications from SARS-CoV-2 infection. Vaccination to prevent COVID-19 is recommended, but data on the immunogenicity and safety of COVID-19 vaccines for patients with solid tumours receiving systemic cancer treatment are scarce. Therefore, we aimed to assess the impact of immunotherapy, chemotherapy, and chemoimmunotherapy on the immunogenicity and safety of the mRNA-1273 (Moderna Biotech, Madrid, Spain) COVID-19 vaccine as part of the Vaccination Against COVID in Cancer (VOICE) trial.

Methods: This prospective, multicentre, non-inferiority trial was done across three centres in the Netherlands. Individuals aged 18 years or older with a life expectancy of more than 12 months were enrolled into four cohorts: individuals without cancer (cohort A [control cohort]), and patients with solid tumours, regardless of stage and histology, treated with immunotherapy (cohort B), chemotherapy (cohort C), or chemoimmunotherapy (cohort D). Participants received two mRNA-1273 vaccinations of 100 μg in 0·5 mL intramuscularly, 28 days apart. The primary endpoint, analysed per protocol (excluding patients with a positive baseline sample [>10 binding antibody units (BAU)/mL], indicating previous SARS-CoV-2 infection), was defined as the SARS-CoV-2 spike S1-specific IgG serum antibody response (ie, SARS-CoV-2-binding antibody concentration of >10 BAU/mL) 28 days after the second vaccination. For the primary endpoint analysis, a non-inferiority design with a margin of 10% was used. We also assessed adverse events in all patients who received at least one vaccination, and recorded solicited adverse events in participants who received at least one vaccination but excluding those who already had seroconversion (>10 BAU/mL) at baseline. This study is ongoing and is registered with ClinicalTrials.gov, NCT04715438.

Findings: Between Feb 17 and March 12, 2021, 791 participants were enrolled and followed up for a median of 122 days (IQR 118 to 128). A SARS-CoV-2-binding antibody response was found in 240 (100%; 95% CI 98 to 100) of 240 evaluable participants in cohort A, 130 (99%; 96 to >99) of 131 evaluable patients in cohort B, 223 (97%; 94 to 99) of 229 evaluable patients in cohort C, and 143 (100%; 97 to 100) of 143 evaluable patients in cohort D. The SARS-CoV-2-binding antibody response in each patient cohort was non-inferior compared with cohort A. No new safety signals were observed. Grade 3 or worse serious adverse events occurred in no participants in cohort A, three (2%) of 137 patients in cohort B, six (2%) of 244 patients in cohort C, and one (1%) of 163 patients in cohort D, with four events (two of fever, and one each of diarrhoea and febrile neutropenia) potentially related to the vaccination. There were no vaccine-related deaths.

Interpretation: Most patients with cancer develop, while receiving chemotherapy, immunotherapy, or both for a solid tumour, an adequate antibody response to vaccination with the mRNA-1273 COVID-19 vaccine. The vaccine is also safe in these patients. The minority of patients with an inadequate response after two vaccinations might benefit from a third vaccination.

Funding: ZonMw, The Netherlands Organisation for Health Research and Development.

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Conflict of interest statement

Declaration of interests SFO reports research grants from Novartis and Celldex Therapeutics, and consultancy fees from Bristol Myers Squibb (BMS; all paid to the institution). AAMvdV reports consultancy fees from BMS, Merck Sharpe & Dohme (MSD), Merck, Sanofi, Eisai, Pfizer, Ipsen, Roche, Pierre Fabre and Novartis, and travel support from Bayer, Roche, Novartis, and Pfizer (all paid to the institution). A-MCD reports consultancy fees from Roche, Boehringer Ingelheim, Amgen, Bayer, Pharmamar, and Sanofi (all paid to the institution); speaker fees from Eli Lilly, AstraZeneca, Jansen, Chiesi, and Takeda (all paid to the institution); and research support from BMS, AbbVie, and Amgen (all paid to the institution). EFS reports consultancy fees from Eli Lilly (all paid to the institution); speaker fees from AstraZeneca, Boehringer Ingelheim, and Daiichi Sankyo (all paid to the institution); and advisory board fees from AstraZeneca, Bayer, BMS, MSD, Merck, Novartis, Pfizer, Roche Genentech, Roche Diagnostics, and Takeda (all paid to the institution). TJNH reports advisory board fees from BMS, AstraZeneca, Merck, Pfizer, Roche, and MSD (all paid to the institution). MJ reports consultancy fees from AstraZeneca and Pierre Fabre (all paid to the institution). GFR reports funding from the Alexander von Humboldt Foundation (paid to the institution). CUB reports an advisory role at BMS, MSD, Roche, Novartis, GlaxoSmithKline, AstraZeneca, Pfizer, Lilly, GenMab, Pierre Fabre, and Third Rock Ventures; research funding from BMS, MSD, 4SC, Novartis, and NanoString (all paid to the institution); stock ownership in Uniti Cars; and being co-founder of Immagene BV. MPGK reports funding from the EU's Horizon H2020 grant (paid to the institution). JBAGH reports consultancy fees from Achilles Therapeutics, BioNTech, BMS, Immunocore, Instil Bio, Molecular Partners, MSD, Gadeta, Merck Serono, Neogene Therapeutics, Novartis, Pfizer, PokeAcel, Roche/Genentech, Sanofi, and T-Knife (paid to the institution); consultancy fees from Neogene Tx; speaker fees from Ipsen, Eisai, and Novartis (paid to the institution); research grants from Asher-Bio, BMS, BioNTech, MSD, and Novartis (paid to the institution); and stock in Neogene Tx. EGEdV reports an advisory role at Daiichi Sankyo, NSABP, and Sanofi, and research funding from Amgen, AstraZeneca, Bayer, Chugai Pharma, Crescendo, CytomX Therapeutics, G1 Therapeutics, Genentech, Nordic Nanovector, Radius Health, Regeneron, Roche, Servier, and Synthon (all paid to the institution). All other authors declare no competing interests.

Figures

Figure 1
Figure 1
Study disposition of all participants included in the study Participants without cancer were included in cohort A, and patients with solid tumours receiving immunotherapy were included in cohort B, those receiving chemotherapy were included in cohort C, and those receiving chemoimmunotherapy were included in cohort D.
Figure 2
Figure 2
SARS-CoV-2-binding antibody concentrations Participants without cancer were included in cohort A, and patients with solid tumours receiving immunotherapy were included in cohort B, those receiving chemotherapy were included in cohort C, and those receiving chemoimmunotherapy were included in cohort D. (A) Distribution of SARS-CoV-2-binding antibody concentrations in log10-transformed BAU/mL at day 28 after second vaccination in the different cohorts. The red solid lines indicate the mean of the log10-transformed BAU/mL concentrations (ie, geometric mean). The red horizontal dashed lines indicate the following: the bottom line represents the threshold for non-responders (SARS-CoV-2-binding antibody concentration ≤10 BAU/ mL), and the top line represents the threshold between suboptimal and adequate responders (>300 BAU/mL). (B) Scatterplot of SARS-CoV-2-binding antibody concentrations in log10 transformed BAU/mL at day 28 after second vaccination versus SARS-CoV-2-binding antibody concentrations in log10 transformed BAU/mL at second vaccination day in the different cohorts. BAU=binding antibody units.
Figure 3
Figure 3
SARS-CoV-2 spike-specific IFNγ T-cell response Participants without cancer were included in cohort A, and patients with solid tumours receiving immunotherapy were included in cohort B, those receiving chemotherapy were included in cohort C, and those receiving chemoimmunotherapy were included in cohort D. (A) The number of SARS-CoV-2 spike-specific IFNγ-producing SFCs per 106 PBMCs at baseline and day 28 after second vaccination in participants selected for T-cell response measurement in the four different cohorts (the red line indicates the median). (B) The number of SARS-CoV-2 spike-specific IFNγ-producing SFCs per 10 PBMCs at baseline and day 28 after second vaccination for non-responders, suboptimal responders, and selected adequate responders (the red horizontal line indicates the median). IFNγ=interferon-γ. PBMCs=peripheral blood mononuclear cells. SFCs=spot-forming cells.
Figure 4
Figure 4
Solicited adverse events in participants who received at least one vaccination and had no seroconversion at baseline Participants without cancer were included in cohort A, and patients with solid tumours treated with immunotherapy were included in cohort B, those treated with chemotherapy were included in cohort C, and those treated with chemoimmunotherapy were included in cohort D. Horizontally stacked bar plot showing the percentage of participants reporting solicited systemic and local adverse events up to 7 days after the first and second vaccination. The highest reported grade during the 7 days after each vaccination was included. Solicited systemic and local adverse events that were reported already at baseline were excluded. Mild indicates not interfering with daily activities, moderate indicates interfering with daily activities, and severe indicates could not perform daily activities for joint pain, fatigue, chills, headache, myalgia, nausea, and pain at injection site. For fever, mild indicates a temperature of 38·0–38·4°C, moderate indicates 38·5–38·9°C, and severe indicates 39·0°C or above. For size of erythema and induration at injection site, mild indicates 2·5–5·0 cm, moderate indicates 5·1–10·0 cm, and severe indicates larger than 10·0 cm.
Figure 4
Figure 4
Solicited adverse events in participants who received at least one vaccination and had no seroconversion at baseline Participants without cancer were included in cohort A, and patients with solid tumours treated with immunotherapy were included in cohort B, those treated with chemotherapy were included in cohort C, and those treated with chemoimmunotherapy were included in cohort D. Horizontally stacked bar plot showing the percentage of participants reporting solicited systemic and local adverse events up to 7 days after the first and second vaccination. The highest reported grade during the 7 days after each vaccination was included. Solicited systemic and local adverse events that were reported already at baseline were excluded. Mild indicates not interfering with daily activities, moderate indicates interfering with daily activities, and severe indicates could not perform daily activities for joint pain, fatigue, chills, headache, myalgia, nausea, and pain at injection site. For fever, mild indicates a temperature of 38·0–38·4°C, moderate indicates 38·5–38·9°C, and severe indicates 39·0°C or above. For size of erythema and induration at injection site, mild indicates 2·5–5·0 cm, moderate indicates 5·1–10·0 cm, and severe indicates larger than 10·0 cm.
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