On Dec 20, 2020, the Israeli Ministry of Health launched a national COVID-19 vaccination
campaign that aimed to rapidly vaccinate all high-risk individuals by the end of January,
2021, using the Pfizer BNT162b2 mRNA vaccine.1, 2 Vaccines were readily available
and free of charge. Patients with cancer who have been treated with systemic anticancer
therapy are at a significantly increased risk of mortality from COVID-19,3, 4, 5,
6 and therefore should be considered as a high-priority group for COVID-19 vaccination.
Because the pivotal vaccination study for BNT162b2 included only healthy individuals
or those with stable chronic medical conditions,
1
a major obstacle faced by the Ministry of Health and by the National Council for the
Prevention Diagnosis and Treatment of Malignant Disease was an absence of data regarding
the safety and efficacy of the vaccine in patients with cancer who have been or are
being treated. Based on available knowledge regarding other routinely used vaccines
(eg, the influenza vaccine) the Ministry of Health recommended vaccination of all
patients with cancer.
7
However, some experts at the National Council raised concerns regarding the ability
of the vaccine to provoke or enhance immune-related side-effects in patients who are
being treated with immune checkpoint inhibitors. Thus, the Ministry of Health left
the decision about vaccinating individuals treated with immune checkpoint inhibitors
to the discretion of their treating physician.
The institutional policy of the Oncology Division at the Tel Aviv Sourasky Medical
Center (TLVMC) and at the Oncology Unit at Bnei-Zion Medical Center was to allow and
encourage vaccination for all patients with cancer being actively treated, regardless
of treatment type. Because COVID-19 is particularly dangerous to these susceptible
patients, vaccination was encouraged regardless of disease stage, performance status,
or life expectancy. Only patients previously infected with SARS-CoV-2 or those with
acute conditions (ie, active infection or active, uncontrolled immune-related side-effects)
were excluded from the vaccination campaign. The vaccine was administered at the standard
recommended dose on days 1 and 21. The second dose was omitted if the patient contracted
SARS-CoV-2 infection after the first dose.
Due to the aforementioned safety concerns, side-effects among patients being treated
with immune checkpoint inhibitors were monitored via detailed telephone questionnaires
done 17–21 days after the first vaccine dose and at a median of 19 days (IQR 12–13)
after the second vaccine dose. Here we report on the safety of the BNT162b2 mRNA vaccine
in a cohort of patients treated with immune checkpoint inhibitors at the two participating
institutions. We compared side-effects in the patients treated with immune checkpoint
inhibitors with a control group. At the beginning of the national campaign, all staff,
including volunteers, at TLVMC were encouraged to receive the BNT162b2 mRNA vaccine
and 2241 vaccinated staff members also participated in the side-effect survey. Each
patient with cancer who had received the second vaccine dose was matched by sex and
year of birth to a healthy individual from among the TLVSMC cohort. The only patient
who was not matched by year of birth was aged 93 years, and they were matched with
a TLVMC volunteer aged 89 years.
Between Jan 11 and Feb 25, 2021, 170 patients who were being treated with immune checkpoint
inhibitors were offered the vaccine and surveyed. 33 (19%) refused the vaccination,
mostly due to fear of side-effects. 137 (81%) patients received the first vaccination
dose, of whom 134 (98%) received the second dose. Three patients died after the first
dose, one due to COVID-19, and two due to disease progression. Characteristics of
the remaining 134 patients are presented in the appendix p 1. The most common side-effects
after the first dose were local, with 28 (21%) of 134 patients reporting pain at the
site of injection. Systemic side-effects included fatigue (five [4%]), headache (three
[2%]), muscle pain (three [2%]), and chills (one [1%]).
During the observation period after the second dose, four (3%) of 134 patients were
admitted to hospital, three due to cancer-related complications and one due to fever,
and all were discharged after treatment. As previously reported,
1
more systemic and local side-effects were observed after the second dose of vaccine
than after the first dose. The most common local side-effects were pain at the injection
site (85 [63%] of 134), local rash (three [2%]), and local swelling (12 [9%]), whereas
the most common systemic side-effects were muscle pain (46 [34%]), fatigue (45 [34%]),
headache (22 [16%]), fever (14 [10%]), chills (14 [10%]), gastrointestinal complications
(14 [10%]), and flu-like symptoms (three [2%]; figure
; appendix p 2). None of the reported side-effects required admission to hospital
or any other special intervention.
Figure
Systemic side-effects after the second dose of the BNT162b2 mRNA vaccine among patients
with cancer treated with immune checkpoint inhibitors and matched controls
ICI=patients with cancer treated with immune checkpoint inhibitors. Bars show the
proportion of participants reporting on each side-effect. Differences between the
groups were calculated using the χ2 test.
Most patients (116 [87%]) were treated with immune checkpoint inhibitors alone and
18 (13%) were treated with a combination of immune checkpoint inhibitors and chemotherapy.
A similar rate of systemic side-effects was observed in both treatment groups (37
[32%] of 116 vs eight [44%] of 18; χ2 test p=0·29).
Most importantly, no new immune-related side-effects or exacerbation of existing immune-related
side-effects were observed.
The side-effect profile was similar in the healthy controls and the patients with
cancer, apart from muscle pain, which was significantly more common among patients
with cancer (figure). However, no immune-related myositis was diagnosed after the
vaccine in either patients or controls. This observation further supports the safety
of the BNT162b2 mRNA vaccine in patients with cancer being treated with immune checkpoint
inhibitors.
The potential association between previous immune-related side-effects and the vaccine
side-effects was also examined. 72 (54%) of 134 patients had previously had grade
2 or worse immune checkpoint inhibitor-related side-effects before they had the vaccine.
There was no significant difference in the number of patients who reported systematic
side-effects after the second dose of vaccine between those who had reported previous
immune-related side-effects and those who had not (24 [33%] of 72 vs 21 [34%] of 62;
p=0·94). Importantly, even in patients with previous immune-related side-effects,
the vaccine-related side-effects were mild and did not lead to admission to hospital
or cessation of cancer treatment.
Little data are available regarding the safety of various vaccines in the context
of treatment with immune checkpoint inhibitors, but vaccination had generally been
suggested to be safe in this population.
8
For example, the influenza vaccine was found to be safe in 370 patients with cancer
actively treated with immune checkpoint inhibitors.
9
Our data support the short-term safety of the BNT162b2 mRNA COVID-19 vaccine in patients
with cancer being treated with immune checkpoint inhibitors. Because no vaccine-related
or immune checkpoint inhibitor-related severe adverse events were observed in this
cohort of 134 patients who received two doses of the vaccine, it is unlikely that
any common side-effects were missed. However, rare side-effects might be identified
when larger cohorts are investigated. Considering the high mortality of patients with
cancer who contract COVID-19, which can be as high as 40% in some patient populations,
3
the benefits of vaccination seem to outweigh the potential harms. Although further
studies are needed to determine if these data are also applicable to the other COVID-19
vaccines, our findings might provide some reassurance for their use in patients being
treated with immune checkpoint inhibitors.
Obviously, larger studies over longer periods of follow-up are required to fully assess
the benefits and harms of vaccines against COVID-19. However, the decision to vaccinate
patients in regions severely affected by the pandemic cannot wait for the accumulating
data from well designed, prospective clinical trials. Thus, despite the absence of
evidence, the March 5, 2021, update of the American Society of Clinical Oncology guidelines
state that “At this time, patients undergoing treatment may be offered vaccination
against COVID-19 as long as any components of the vaccine are not contraindicated”.
The data we present here provide, for the first time, a reassuring safety signal regarding
the BNT162b2 mRNA COVID-19 vaccine in patients with cancer treated with immune checkpoint
inhibitors. Considering the high mortality due to COVID-19 in patients with cancer
who are being treated, our data support current guidelines and call for vaccination
of patients being treated with immune checkpoint inhibitors, especially during pandemic
surges.
IW and BW contributed to conception and design of the study. BW, AA, ES, and HP contributed
to collection and analysis of data. BW and IW contributed to data analysis and interpretation.
All authors contributed to writing of the Comment and approved the final version before
submission. This study had no funding. BW reports speaker fees and fees for consultancy
from MSD. AA reports speaker fees and fees for consultancy from MSD, Roche, Boehringer
Ingelheim, AstraZeneca, Eli Lilly, Pfizer, Bristol Meyers Squibb, Novartis, Merck
Serono, Sanofi, Oncotest-Teva, Medison, AbbVie, and Takeda; grants from Altman Health;
and is a member of the board for the Israeli Lung Cancer Advocacy Group. IW reports
speaker fees and fees for consultancy from Roche, Bristol Myers Squibb, MSD, and Novartis,
and research funding from Roche and MSD. ES and HP declare no competing interests.
No individual participant-level data will be shared.