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. 2022 Dec 30:10.1111/1348-0421.13043. Online ahead of print. doi: 10.1111/1348-0421.13043

Comparison of cytokine production in mice inoculated with messenger RNA vaccines BNT162b2 and mRNA‐1273

Tetsuo Nakayama 1,✉, Akihito Sawada 1, Takeshi Ito 1,2
PMCID: PMC9878178  PMID: 36480238

Abstract

Two messenger RNA (mRNA) vaccines of BNT162b2 and mRNA‐1273 were licensed. The most common adverse event is regional pain at the injection site in 80%. As systemic reactions, fatigue and headache were noted in 40%–60% and febrile illness in 10%–40% of the recipients. To investigate the mechanism of adverse events, cytokine profiles were investigated in mice. Muscle tissue and serum samples were obtained on days 0, 1, 3, 5, and 7, and at 2 and 4 weeks after the first dose. The second dose was given 4 weeks after the first dose and samples were obtained. After inoculation with 0.1 mL of mRNA‐1273, IFN‐γ and IL‐2 were detected in muscle tissues and serum samples on day 1 of the second doses, and similar profiles were observed for IL‐4, IL‐5, and IL‐12 production. mRNA‐1273 induced higher levels of Th1 and Th2 cytokines. TNF‐α was induced in muscle tissues on day 1 of the first dose and enhanced on day 1 of the second dose after inoculation with BNT162b2 and mRNA‐1273. IL‐6 was also detected in muscle tissue on day 1 of the first dose, but it decreased after day 3, and enhanced production was demonstrated on day 1 of the second dose. Granulocyte colony‐stimulating factor in muscle tissues showed a similar profile. The induction of inflammatory cytokines in the mouse model is related to the cause of adverse events in humans, with a higher incidence of adverse events after the second dose.

Keywords: adverse events, inflammatory cytokine, mRNA vaccine, Th1/Th2 cytokine

Abbreviations

COVID‐19

coronavirus disease 2019

G‐CSF

granulocyte colony‐stimulating factor

LNP

lipid nanoparticle

mRNA

messenger RNA

RPMI

Roswell Park Memorial Institute

SARS‐CoV‐2

severe acute respiratory syndrome coronavirus‐2

INTRODUCTION

An unknown pneumonia outbreak was reported by the World Health Organization (WHO) from Wuhan, China on December 31, 2019. The full‐length nucleotide sequence was mapped on January10, 2020, and the pathogen was named severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) with morphological similarity to SARS that occurred in 2002. Initially, the majority of patients infected with SARS‐CoV‐2 (coronavirus disease 2019 [COVID‐19]) were linked to the regional live wild animal markets where SARS‐CoV‐2 virus was isolated from. However, early cases of COVID‐19 had no epidemiological connection to the market. Two different lineages of SARS‐CoV‐2 were identified and caused a regional outbreak in Wuhan, expanding to the whole of China. Up until February 11, 2020, 44,672 cases were reported, and the case fatality rate was 2.3% with higher levels in elderly. 1 , 2

It spread to the European Union and United States within a few months through mostly travelers infected in China, and domestic spread had begun in several countries and the WHO declared a pandemic alert on March 11, 2020. 1 , 2 , 3 The case fatality rate was around 2%–4%, lower than SARS‐CoV‐1 or Middle East respiratory syndrome, but the transmission rate of SARS‐CoV‐2 was much higher, with asymptomatic infections as a transmitter. 1 , 2 , 3 Therefore, the rapid development of effective vaccines was expected, and messenger RNA (mRNA) and virus‐vectored vaccines were developed and licensed for emergency use in December 2020 in the United States. BNT162b2 (Comirnaty; Pfizer‐BioNTech), 4 , 5 mRNA‐1273 (Spikevax; Moderna), 6 , 7 and adenovirus‐vectored vaccine ChAdOx1 (Vaxzevria; AstraZeneca) were licensed. 8 , 9 Two mRNA vaccines have been used since February 2021 in Japan. BNT162b2, containing 30 μg mRNA/0.3 mL, has been mainly used with less usage of mRNA‐1273, containing 100 μg mRNA/0.5 mL, and they were embedded in lipid nanoparticle (LNP). RNA is a ligand of TLR3, 7, and 8 of pattern recognition receptors of innate immunity, and LNP stimulates damage‐associated molecular patterns. 10 , 11 Acquired immunity develops through activation of innate immunity. Although they induced protective immune responses, local pain was reported in approximately 80% of recipients, and fatigue and headache were noted in 40%–60% and febrile illness in 10%–40% of the recipients as systemic reactions. 4 , 5 , 6 , 7 Some young individuals hesitate to receive mRNA and ChAdOX1 vaccines, worrying about regional pain, fever, and serious adverse events of carditis and pericarditis. 12 , 13

We previously reported that inflammatory nodules were observed after immunization with adjuvanted vaccines in mice, and inflammatory cytokines were detected from 3 to 48 h after immunization with diphtheria tetanus toxoids with pertussis, Hemophilus influenzae type B, pneumococcal conjugated vaccine, and human papilloma virus. 14 , 15 LNP of mRNA vaccines forms similar oil morphology to the ASO1B liposome adjuvant system. 16 , 17 Varicella zoster virus vaccine (Shingrix; GSK) contains recombinant gE protein of varicella zoster virus with AS01B. 18 They promote inflammatory reactions after vaccination, and acquired immune responses develop through inflammatory reactions. Th2 cytokines and inflammatory cytokines were detected in mice inoculated with Shingrix on day 1 of the first and second doses. 19 The purpose of the present study was to investigate the cytokine profiles in a mouse model to elucidate the adverse events associated with local and systemic adverse events after immunization with two mRNA vaccines.

MATERIALS AND METHODS

Study plan

Female BALB/c mice aged 4 weeks were purchased from Charles River Laboratory (The Jackosn Laboratories Japan, Yokohama, Japan) and inoculated with 0.1 mL BNT162b2 or mRNA‐1273. The experimental schedule is shown in Figure 1. Muscle tissues and serum samples were collected from three mice at each timepoint on days 0, 1, 3, 5, and 7, and at 2 and 4 weeks after the first dose. The second dose was given at 4 weeks after the first dose, and the following samples were obtained in a similar fashion. Thigh muscle tissue was obtained under anesthesia with pentobarbital sodium throughout the experiment timepoints and blood samples were obtained through cardiac puncture at the same time. 15 , 19 Samples were applied for the detection of cytokines. The Ethical Committee of Animal Research of Kitasato University (approval number 21‐036) approved the study protocol.

Figure 1.

Figure 1

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Experimental schedule. Muscle tissues and serum samples were collected from three mice at each timepoint on days 0, 1, 3, 5, and 7, and at 2 and 4 weeks after the first dose. The second dose was given at 4 weeks after the first dose, and the following samples were obtained in a similar fashion. Three mice were used for each timepoint.

Cytokine measurement

Approximately 150 mg of muscle tissues at the same injected site was obtained and homogenized in 1.0 mL of RPMI (Roswell Park Memorial Institute, Sigma‐Aldrich, UK) medium supplemented with 1% protease inhibitor (Nacalai Tesque, Kyoto, Japan) using Precellys Lysing Kits (BERTIN Corp., Bertin Technologies, France). The muscle homogenate was centrifuged, filtrated through a 0.45‐μm filter, and stored at −80°C until assay. They were assayed in the same plate. G‐CSF, IFN‐γ, IL‐2, IL‐4, IL‐5, IL‐10, IL‐12, and TNF‐α were measured using the Bio‐Plex mouse cytokine Th1/Th2 panel (Bio‐Plex; BIO‐RAD Laboratories, USA). Granulocyte colony‐stimulating factor (G‐CSF) and IL‐6 were, respectively, assayed using mouse G‐CSF and mouse IL‐6 SimpleStep ELISA Kits (Abcam, UK). 15 , 19 Stocked serum samples were also subjected to cytokine assays.

Statistical analysis

Cytokine concentrations were analyzed in box‐and‐whisker plots with the median titer and lower and upper range of 5%–95%. Significance (P < 0.05) was determined by the Welch t‐test, using Bell Curve for Excel (Social Survey Research Information Co. Ltd).

RESULTS

Th1 cytokine production in muscle tissues and serum samples

Cytokine production was investigated in mice inoculated with 0.1 mL mRNA‐1273, and the results of Th1 cytokine productions of IFN‐γ, IL‐2, and TNF‐α are shown in Figure 2. The cytokine concentration is shown as the mean ± 1.0 SD. Higher levels of IFN‐γ were detected in serum on day 1 of the second dose (124.07 ± 50.12 pg/mL) than that on day 1 of the first dose (15.56 ± 7.83 pg/mL). Similarly, IFN‐γ in muscle tissue was higher on day 1 of the second dose (24.73 ± 8.07 pg/mL) than that on day 1 of the first dose (2.04 ± 1.47 pg/mL). Similar cytokine profiles of IL‐2 and TNF‐α were observed: higher levels of Th1 cytokines in muscle tissues on day 1 of the second dose than those on day 1 of the first dose. In serum samples, the enhanced level of TNF‐α peaked on day 3 of the second dose.

Figure 2.

Figure 2

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IFN‐γ, IL‐2, and TNF‐α profiles in muscle tissues and serum samples following inoculation with mRNA‐1273. They are shown in box‐and‐whisker plots with median titers and the range of 5%–95%. Samples were obtained before injection, on days 1, 3, 5, and 7, and at 2 and 4 weeks after the first dose. The second dose was administered at 4 weeks and samples were obtained based on the same schedule.

Th2 cytokine production in muscle tissues and serum samples

The results of Th2 cytokine production of IL‐4, IL‐5, IL‐10, and IL‐12 are shown in Figure 3. IL‐4 was detected in muscle tissues on day 1 of the second dose (11.69 ± 5.64 pg/mL). No significant IL‐4 was detected in serum samples. Elevated levels of IL‐5 were detected in serum (1188.32 ± 168.99 pg/mL) and muscle tissues (384.57 ± 111.98 pg/mL) on day 1 of the second dose. IL‐10 gradually increased during 7 days after the first dose in muscle tissues and elevated on day 1 of the second dose (3.47 ± 0.38 pg/mL) with a peak increase on day 3 of the second dose (6.79 ± 0.53 pg/mL). High levels of IL‐10 were noted in serum samples on day 1 of the first dose (23.62 ± 10.00 pg/mL) but not enhanced after the second dose. IL‐12 production in serum was observed on day 3 (5.69 ± 4.89 pg/mL) and enhanced on day 5 (14.43 ± 7.29 pg/mL) after the second dose.

Figure 3.

Figure 3

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IL‐4, IL‐5, IL‐10, and IL‐12 profiles in muscle tissues and serum samples following inoculation with mRNA‐1273. They are shown in box‐and‐whisker plots with median titers and the range of 5%–95%. Samples were obtained before injection, on days 1, 3, 5, and 7, and at 2 and 4 weeks after the first dose. The second dose was administered at 4 weeks and samples were obtained based on the same schedule.

Comparison of cytokine production following inoculation with mRNA‐1273 and BNT162b2

Cytokine production was also investigated following inoculation with BNT162b2, compared with mRNA‐1273 inoculation. IFN‐γ production in muscle tissue and serum samples is shown in Figure 4. IFN‐γ production on day 1 of the first dose in muscle tissues inoculated with BNT162b2 (6.68 ± 3.44 pg/mL) was similar to that in those inoculated with mRNA‐1273 (2.04 ± 1.47 pg/mL). As for day 1 of the second dose, IFN‐γ was lower in muscle tissue following BNT162b2 (12.16 ± 5.28 pg/mL) than following mRNA‐1273 (24.73 ± 8.07 pg/mL), but this was not significant.

Figure 4.

Figure 4

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Comparison of IFN‐γ production in muscle tissues and serum samples following inoculation with mRNA‐1273 and BNT162b2. They are shown in box‐and‐whisker plots with median titers and the range of 5%–95%. Samples were obtained before injection, on days 1, 3, 5, and 7, and at 2 and 4 weeks after the first dose. The second dose was administered at 4 weeks and samples were obtained based on the same schedule. Serum IFN‐γ on day 1 of the first and second doses following inoculation with mRNA‐1273 was higher than with BNT162b2. (*P < 0.05)

In serum samples on day 1 of the first dose of BNT162b2, IFN‐γ production was 4.81 ± 1.74 pg/mL, being significantly lower than 15.56 ± 7.84 pg/mL following mRNA‐1273 (P < 0.05). As for on day 1 of the second dose, IFN‐γ production was 14.48 ± 16.03 pg/mL following inoculation with BNT162b, being lower than that after inoculation with mRNA‐1273 (124.07 ± 50.12 pg/mL; P < 0.05).

Serum IL‐5 was significantly higher on day 1 of the second dose following inoculation with mRNA‐1273 (1188.32 ± 168.99 pg/mL) than on the same timepoint after inoculation with BNT162b2 (24.09 ± 3.64 pg/mL; P < 0.01; Figure 5). The TNF‐α profile following BNT162b2 inoculation in muscle tissues was similar to that following inoculation with mRNA‐1273 (Figure 5).

Figure 5.

Figure 5

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Comparison of serum IL‐5 and muscle TNF‐α production following inoculation with mRNA‐1273 and BNT162b2. They are shown in box‐and‐whisker plots with median titers and the range of 5%–95%. Samples were obtained before injection, on days 1, 3, 5, and 7, and at 2 and 4 weeks after the first dose. The second dose was administered at 4 weeks and samples were obtained based on the same schedule. Serum IL‐5 on day 1 of the second dose following inoculation with mRNA‐1273 was higher than following that with BNT162b2 (**P < 0.01).

Inflammatory cytokines of IL‐6 and G‐CSF production were compared in muscle tissues and the results are shown in Figure 6. IL‐6 on day 1 of the first dose following BNT162b2 (674.19 ± 286.82 pg/mL) was higher than that following mRNA‐1273 (208.65 ± 53.66 pg/mL). A higher level of IL‐6 was detected on day 1 of the second dose of BNT162b2 (1604 ± 954.73 pg/mL) than that observed following inoculation with mRNA‐1273 (532.63 ± 126.88 pg/mL), but this was not significant. The G‐CSF profile in muscle tissues was also examined following both BNT162b2 and mRNA‐1273, and higher levels of G‐CSF were noted on day 1 of the second dose than on day 1 of the first dose, without a significant difference between the two mRNA vaccines.

Figure 6.

Figure 6

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Comparison of IL‐6 and G‐CSF in muscle tissues following inoculation with mRNA‐1273 and BNT162b2. They are shown in box‐and‐whisker plots with median titers and the range of 5%–95%. Samples were obtained before injection, on days 1 and 3 after the first dose. The second dose was administered at 4 weeks and samples were obtained based on the same schedule.

Mice in both groups injected with mRNA‐1273 or BNT162b2 had no symptoms without loss of appetite or decrease in activity.

DISCUSSION

The incidence of adverse events following immunization with human papilloma virus vaccine was higher than that after the conventional vaccines of diphtheria–tetanus–pertussis, H. influenzae type B, pneumococcal conjugated vaccine, influenza, and Japanese encephalitis virus vaccines. 20 , 21 We investigated the inflammatory cytokines following inoculation in the mouse model. 14 , 15 Among them, inflammatory nodules developed after alum‐adjuvanted vaccines, but not after nonadjuvanted vaccines. Inflammatory nodules consisted of migrated neutrophils or macrophages, and they developed neutrophil extracellular traps. 15 DNA and/or reactive oxygen species stimulate damage‐associated molecular patterns, inducing inflammatory cytokines: IL‐1β, IL‐6, and TNF‐α. 15 The time course of inflammatory cytokines was investigated. IL‐1β, IL‐6, G‐CSF, and MCP‐1 were produced from 3 h and peaked at 48 h after immunization with Cervarix in mouse muscle tissues. IL‐4, MCP‐1, and TNF‐α peaked at 5 or 7 days after immunization with Gardasil. These cytokines decreased 7 days after immunization with Cervarix and Gardasil. 15 These inflammatory cytokine profiles in mouse experiments were related to local adverse reactions. Serum cytokine profiles following immunization with Cervarix and Gardasil were also investigated. MCP‐1 and TNF‐α were detected at 6 h and IL‐1β at 6–24 h after immunization with Gardasil and decreased after day 7 of immunization, while being enhanced on day 5 of reimmunization. 15 In 2017, Shingrix was licensed for varicella zoster in the United States, and in Japan in 2020, with a recommendation for use in the elderly aged 50 years and over. 22 However, there were concerns about serious regional pain at the injection site, caused by the AS01B adjuvant system, using monophosphoryl lipid A, Quillaja saponaria Molina extract QS‐21, cholesterol, and dioleoylphosphatidylcholine in the composition of liposomes. To elucidate the pathogenesis, cytokine profiles were examined. IL‐6 and G‐CSF were detected in muscle tissues on day 1 of the first injection, decreased on day 3 and afterward, and enhanced production was demonstrated on day 1 of the second dose. In sera, the elevated levels of IL‐6 were detected on day 1 of the first dose, and IL‐10 was detected on day 1 with increased levels on day 3 of the first dose. 19

Through rapid transmission of COVID‐19, the development of an effective vaccine was expected. 23 mRNA vaccines were introduced for emergency use with unexpectedly high efficacy in a phase III test. 4 , 5 , 6 , 7 Local pain at the injection site was reported by approximately 80% of recipients and, as systemic reactions, fatigue and headache were noted in 40%–60% with febrile illness in 10%–40% of the recipients, with a higher incidence after the second dose. 4 , 5 , 6 , 7 As a matter of importance, the incidence of myocarditis was higher after immunization with mRNA‐1273 in comparison with BNT162b2. 12 , 13 However, the causal mechanism of myocarditis following immunization with mRNA vaccines has not been elucidated. Some theories advocate regional cardiac effects of systemic inflammation mediated by IFN or inflammatory cytokines 24 , 25 or cardiac protein mimicry elicited by an autoimmune response. 26 Several cases with myocarditis were reported to be associated with postinfection hyperinflammatory syndrome and multisystem inflammatory syndrome in children with COVID‐19. 27 From this point of view, cytokine profiles were investigated and IFN‐γ and IL‐2 were elevated in muscle tissue and serum samples on day 1 of the second dose. Serum IL‐4 and IL‐5 in muscle tissues, and serum samples were elevated on day 1 of the second dose. IL‐10 increased during the 7 days after the first dose and elevated on days 1 and 3 after the second dose. IL‐10 elevated on day 1 of the first dose in serum samples.

In comparison with cytokine profiles of mRNA‐1273 and BNT162b2, there was no significant difference in the IFN‐γ profiles in muscle tissues. However, significantly higher IFN‐γ was detected in serum on day 1 of the first and second doses following inoculation with mRNA‐1273 than that following BNT162b2 (P < 0.05). Besides, mRNA‐1273 induced higher levels of serum IL‐5 on day 1 of the second dose than following BNT162b2 (P < 0.01). TNF‐α, IL‐6, and G‐CSF in muscle tissues were elevated on day 1 of the second dose, compared with on day 1 of the first dose. No significant difference was observed following inoculation with mRNA‐1273 and following BNT162b2. These cytokine profiles can explain the high incidence of local adverse events after vaccination with a similar incidence following immunization with mRNA‐1273 or BNT162b2. Levels of several cytokines including IFN‐γ were more elevated following inoculation with mRNA‐1273 than following BNT162b2. This could reflect the higher incidence of adverse events associated with mRNA‐1273.

CONCLUSION

mRNA vaccines induced TNF‐α, IL‐6, and G‐CSF in muscle tissues on day 1 of injection in mice after the first dose and levels were enhanced on day 1 of the second dose. However, there was no significant difference in inflammatory cytokines following inoculation with mRNA‐1273 or BNT162b2, which may explain local pain after immunization occurring at a similar incidence of 80%. Th1 and Th2 cytokine production was enhanced after the second dose, reflecting an increased incidence of adverse events in humans.

AUTHOR CONTRIBUTIONS

Animal studies: Akihito Sawada and Takeshi Ito. Cytokine assay: Tetsuo Nakayama and Takeshi Ito. Preparing manuscript, funding acquisition, and statistical analysis: Tetsuo Nakayama. All authors have read and agreed to the published version of the manuscript.

DISCLOSURE

The authors declare no conflict of interest.

ETHICS STATEMENT

The Ethical Committee of Animal Research of Kitasato University (approval number 21‐036, dated on May 10, 2021) approved this animal study protocol.

ACKNOWLEDGMENTS

The study was supported by the Japan Agency for Medical Research and Development (AMED; Grant Number 20fk0108099s0202; Chief Investigator: Shigeru Suga, Department of Pediatrics, National Mie Hospital).

Nakayama T, Sawada A, Ito T. Comparison of cytokine production in mice inoculated with messenger RNA vaccines BNT162b2 and mRNA‐1273. Microbiol Immunol. 2022;1–9. 10.1111/1348-0421.13043

DATA AVAILABILITY STATEMENT

Data available on request from the authors.

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Data Availability Statement

Data available on request from the authors.

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