key: cord-0695179-5rufrk7y
authors: Funakoshi, Yohei; Yakushijin, Kimikazu; Ohji, Goh; Hojo, Wataru; Sakai, Hironori; Takai, Ryo; Nose, Taku; Ohata, Shinya; Nagatani, Yoshiaki; Koyama, Taiji; Kitao, Akihito; Nishimura, Meiko; Imamura, Yoshinori; Kiyota, Naomi; Harada, Kenichi; Tanaka, Yugo; Mori, Yasuko; Minami, Hironobu
title: Safety and Immunogenicity of the COVID-19 vaccine BNT162b2 in patients undergoing chemotherapy for solid cancer
date: 2021-12-30
journal: J Infect Chemother
DOI: 10.1016/j.jiac.2021.12.021
sha: abe4b773ca9f0076d12f9de789001c122e3f258d
doc_id: 695179
cord_uid: 5rufrk7y

BACKGROUND: Although COVID-19 severity in cancer patients is high, the safety and immunogenicity of the BNT162b2 mRNA COVID-19 vaccine in patients undergoing chemotherapy for solid cancers in Japan have not been reported. METHODS: We investigated the safety and immunogenicity of BNT162b2 in 41 patients undergoing chemotherapy for solid cancers and in healthy volunteers who received 2 doses of BNT162b2. We evaluated serum IgG antibody titers for S1 protein by ELISA at pre-vaccination, prior to the second dose and 14 days after the second vaccination in 24 cancer patients undergoing cytotoxic chemotherapy (CC group), 17 cancer patients undergoing immune checkpoint inhibitor therapy (ICI group) and 12 age-matched healthy volunteers (HV group). Additionally, inflammatory cytokine levels were compared between the HV and ICI groups at pre and the next day of each vaccination. RESULTS: Anti-S1 antibody levels were significantly lower in the ICI and CC groups than in the HV group after the second dose (median optimal density: 0.241 [0.063–1.205] and 0.161 [0.07–0.857] vs 0.644 [0.259–1.498], p = 0.0024 and p < 0.0001, respectively). Adverse effect profile did not differ among the three groups, and no serious adverse event occurred. There were no differences in vaccine-induced inflammatory cytokines between the HV and ICI groups. CONCLUSION: Although there were no significant differences in adverse events in three groups, antibody titers were significantly lower in the ICI and CC groups than in the HV group. Further protection strategies should be considered in cancer patients undergoing CC or ICI.

Compared with individuals with the corona virus disease 2019 (COVID-19) without cancer, individuals with COVID-19 and cancer have been characterized as having severe outcomes and mortality [1, 2] . In a meta-analysis of 52 studies involving 18,650 patients with COVID-19 and cancer, the incidence of mortality was high at 25.6% [3] .

Additionally, some studies raised concerns about the delayed diagnosis of primary and/or recurrent cancers and delayed treatment due to COVID-19 [4] . Accordingly, experts have generally recommended that patients with cancer should receive vaccines to protect against COVID-19.

The BNT162b2 mRNA COVID-19 vaccine that leads to transient expression of the SARS-CoV-2 spike protein was developed in 2020 [5] . The phase 3 trial of the vaccine showed 95% efficacy in preventing symptomatic COVID-19 infection [6] . However, data concerning the efficacy and safety of this vaccine for cancer patients was insufficient, because they were excluded from the initial registration trials [6] .

Most recently, several studies have reported that SARS-CoV-2 antibody titers after vaccination were significantly lower in patients with solid tumors undergoing chemotherapy than in healthy volunteers [7] [8] [9] [10] . Interestingly, given the variation in the major histocompatibility complex molecules, the efficacy of COVID-19 vaccines may vary by race in view of the variation in the major histocompatibility complex molecules J o u r n a l P r e -p r o o f [11] . Further, in a phase III trial of BNT162b2Review Report of BNT162b2 by the Pharmaceuticals and Medical Devices Agency (PMDA) of Japan revealed that, vaccine efficacy appeared to be lower in the Asian populations might be lower than in the total population (74.6 vs 95.0%) [6] . Considering tThese results, emphasize the importance of data collection in different regions and races is important. However, no data on the safety and immunogenicity of the COVID-19 vaccines for cancer patients undergoing chemotherapy have been reported in Japan. Here, we investigated the safety and immunogenicity of BNT162b2 in Japanese patients with solid tumors receiving cytotoxic chemotherapy or immune-checkpoint inhibitor (ICI) therapy.

Additionally, in the assessmentassessing of adverse reactions, we hypothesized that ICI-activated immunity might induce excessive inflammatory effects after BNT162b2.

Even in general population, elevated levels of inflammatory cytokines have been reported after administration of various vaccines, such as the influenza and the human papillomavirus vaccine [12, 13] . Importantly, elevated cytokines were also reported after administration of BNT162b2 in an in vivo study [14] . To test this, we compared levels of various inflammatory cytokines before and the day after each vaccination were compared between the HV and ICI groups. 

J o u r n a l P r e -p r o o f Serum samples were obtained by centrifuging the blood samples for 10 min at 1000 × g at room temperature, and were immediately transferred to a freezer kept at -80°C.

Antibody titers against S1 were measured using the QuaResearch COVID-19

Human IgM IgG ELISA kit (Spike Protein-S1) (Cellspect, Inc., RCOEL961S1, Iwate, Japan). This kit is based on the indirect ELISA method, and comes with different immobilized antigenic proteins. The plate of the ELISA kit (Spike Protein-S1) is immobilized with a recombinant spike protein (S1, 251-660AA) of SARS-CoV-2 expressed in Escherichia coli. Serum samples were diluted 1:200 in 1% BSA/PBST for RCOEL961S1.The plates were read at 450 nm with an SH-1200 plate reader (Corona Electric Co. Ltd.) in accordance with the manufacturer's measurement protocol.

Differences in serum anti-S1 antibody level in the HV, CC and ICI groups after the second dose were compared using the unpaired t-test. P-values <0.05 were considered to be statistically significant. GraphPad Prism version 9.2.0 (GraphPad Software, CA, USA) was used to calculate statistical significance. 

Forty-one Japanese patients with solid tumors and 12 healthy volunteers were enrolled in this study. Among the 41 patients, 24 were undergoing cytotoxic chemotherapy (CC group) and 17 patients were undergoing ICI therapy (ICI group).

Treatments are shown in Table 1 . Among the ICI group, 14 patients were previously treated with cytotoxic chemotherapy with or without radiation therapy and two patients were treated with radiation therapy alone before ICI therapy (Table 1 ). Both groups received the first and second doses of BNT162b2 during the course of these therapies.

Antibody titers after the second dose were significantly higher than those at prevaccination in all groups ( Figure 1A) . However, anti-S1 antibody levels in both the ICI and CC groups were significantly lower than those in the HV group after the second dose Figure 1A and B).

There was no clinical difference in the profile of vaccine-related adverse events among the three groups (Figure 2) , and no serious adverse event (> Grade 3) was reported in any participant.

The impact of vaccination on ICI-activated immunity was investigated by measuring cytokine levels before and the day after each vaccination. However, levels of inflammatory cytokines did not show any significant changes in the HV or ICI groups ( Figure 3) . Results showed no meaningful differences between the two groups.

Because cytotoxic chemotherapy affects bone marrow and suppresses the immune system, concern has been raised that these drugs impair the efficacy of SARS-CoV-2 vaccines in triggering the humoral immune response. Most recently, several study groups reported that antibody titers of patients with cancer who were receiving active systemic chemotherapy were significantly lower than those of healthy volunteers [7] [8] [9] . Consistent with these reports, our Japanese data also indicated that anti-S1 antibody levels in cancer patients treated with active chemotherapy were significantly lower than those observed in the HV group after the second dose. Interestingly, anti-S1 antibody levels were significantly lower in not only the CC group but also in the ICI group. BecauseGiven that the ICI is known to enhances the immune system, this result was unexpected. Another, and similar results to ours were reported by other research groups reported similar results in a small number of cases (n = 14) [7, 15] . It is possible that the effect of cytotoxic chemotherapy and/or RT before ICI therapy and the immunosuppressed state due to malignancy itself suppress antibody production.

Predictive models of immune protection from COVID-19 using serum antibody levels have been reported [16] . However, such models are not well validated and have not been applied in clinical practice. Therefore, Aalthough the presence of lower titers than in healthy volunteers does not prove that humoral immunity has no preventive effect, further J o u r n a l P r e -p r o o f careful protection strategies should be considered in these cancer patients. To protect these patients from COVID-19, we first recommend that they continue to wear a face mask and wash their hands even after vaccination [13, 14] . Second, a third dose (booster dose)the third vaccination with of the COVID-19 vaccines might be effective. The efficacy of three doses has been reported in patients with solid organ transplantation who also have impaired antibody production due to immunosuppressants [15] . We believe that it is important to continue to actively collect and offer information on vaccine efficacy for cancer patients.

Inflammatory reactions including fever have been reported as major adverse reactions after vaccination with mRNA-containing lipid nanoparticles (LNPs) such as BNT162b2.

A study group has reported that vaccines based on mRNA-containing LNPs induced high production of inflammatory cytokines (IL-6, GM-CSF and IL-1β) in mice 24 hours after vaccination [16] . Because we were concerned that ICI-activated immunity might induce excessive inflammatory effects, inflammatory cytokine levels were measured before and after vaccination (Day 2) and compared between the HV and ICI groups. Contrary to the results in the mouse model, there was no trend toward an increase in levels of inflammatory cytokines after vaccination in either the HV group or ICI group, despite our consideration that the immune systems of these patients were activated. Further, cytokine J o u r n a l P r e -p r o o f level was not increased even in patients who had fever after vaccination. Overall, levels of all measured cytokines were low. Consistent with these results, we found no clinical differences in the profile of adverse reactions among the three groups, and no serious adverse event was reported in any participant.

Our study has some limitations. First, because sample size was small, confirmation of these tendencies requires further investigation with a larger number of participants.

Second, although T cell-mediated immune response after vaccination is an also important factor in protection against COVID-19, we did not evaluate this in our study. Third, some clinical information which are expected to be associated with immune activity, such as body mass index, are missing. Finally, although we focused on a Japanese population, we did not set a strict definition of Japanese and did not interview each participant about their racial background. Further, we did not analyze the HLA status of participants.

In conclusion, although there was no significant difference in adverse events in the three groups, antibody titers in Japanese patients treated with cytotoxic chemotherapy and ICI were significantly lower than those in the HV group. Further protection strategies should be considered. 

Gem + nab-PTX 

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The mrna-lnp platform's lipid nanoparticle component used in preclinical vaccine studies is highly inflammatory

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