Adverse Reactions After Intradermal Vaccination With JYNNEOS for Mpox in Korea

Abstract

In response to the Mpox domestic epidemic, South Korea initiated a nationwide vaccination program in May 2023, administering a 0.1 mL intradermal dose of JYNNEOS (Modified Vaccinia Ankara vaccine, Bavarian Nordic) to a high-risk group. To investigate the adverse reactions after intradermal JYNNEOS vaccination, an anonymous online survey was conducted at the National Medical Center from May 22 to July 31, 2023. Overall, 142 individuals responded. Over 80% of the respondents reported local reactions of predominantly mild severity. The predominant local reactions were pruritus, redness, and swelling; their incidence rates after the first dose were 66.2%, 48.1%, and 49.4%, respectively; the corresponding rates after the second dose were 69.2%, 60.6%, and 53.8%. Fewer respondents reported systemic symptoms. The most common systemic symptom was fatigue, the incidence rates of which after the first and second doses were 37.7% and 24.6%, respectively. Overall, the intradermally administered JYNNEOS vaccine appeared well tolerated.

Graphical Abstract

From May 6, 2022, monkeypox virus infections started emerging in parts of Europe and America, regions in which the virus was not previously endemic. Since early April 2023, a notable surge in indigenous Mpox cases without overseas travel history has been observed in South Korea. In response to the domestic Mpox epidemic, a nationwide Mpox vaccination initiative with 0.1 mL intradermal administration of JYNNEOS (Modified Vaccinia Ankara vaccine, Bavarian Nordic) targeting the high-risk population1 was launched in May 2023. Although some safety profiles of the JYNNEOS vaccine have been previously reported,2,3,4 the incidence and severity of adverse reactions resulting from vaccinations can vary based on regional and ethnic factors. Although a recent study showed adverse reactions after subcutaneous JYNNEOS vaccination with a standard dose (0.5 mL) in a small number of healthcare workers in South Korea,5 there have been no comprehensive reports on adverse reactions among the target population at risk after 0.1 mL intradermal JYNNEOS vaccination in South Korea. Thus, we conducted a survey to investigate adverse reactions after the intradermal administration of the first and second doses of the JYNNEOS vaccine for Mpox.

This study was conducted at the National Medical Center, a designated hospital for the nationwide Mpox vaccination program in Seoul, South Korea. For active surveillance, an anonymous online survey using Google Forms was sent to those who received the JYNNEOS vaccine for Mpox and consented to receive text messages regarding post-vaccination adverse reactions between May 22 and July 31, 2023. South Korea’s national policy recommends intradermal vaccination by default; however, subcutaneous vaccination is allowed if there is a history of keloids or if the individual wishes. Participants who received a 0.1 mL intradermal vaccination in their upper arm were exclusively recruited, and an online survey was sent to vaccine recipients 2 and 5 days after each vaccination dose.

The following information was collected from the survey respondents by using a questionnaire: sex, age, vaccine dose, use of antipyretic drugs (both acetaminophen and nonsteroidal anti-inflammatory drugs), and adverse reactions experienced after vaccination. The local adverse reactions included in the survey were pain, pruritus, redness, and swelling at the inoculation site. Systemic adverse reactions included febrile sense, chills, fatigue, headache, myalgia, arthralgia, vomiting, and diarrhea. The severity of the adverse reactions was classified as follows: no symptom, mild, moderate, severe, and required a hospital visit.6 An open-ended question for unsolicited adverse events was also included. The questionnaire items in the survey are described in the Supplementary Data 1.

The intent was to obtain as many responses as possible from those who consented to participate in the survey rather than based on the number of power analyses. Data analyses were performed using R version 4.1.3 (R Project for Statistical Computing, Vienna, Austria). Descriptive analyses were performed using survey results.

During the study period, 376 recipients received the JYNNEOS vaccine (either the first or second dose), and 237 (63%) were people living with HIV. Among 376 recipients, 166 individuals consented to participate in the survey, and 142 (85.5%) responded to active surveillance. Of the 142 individuals, 98.6% were male; the median age was 41 years (interquartile range, 34−49 years). The baseline characteristics of the vaccine recipients and survey respondents are shown in Table 1. Among the respondents, 38.0% were born in 1979 or earlier, i.e., during the era of a nationwide smallpox vaccination program in South Korea.

Table 1. Baseline characteristics of the survey respondents and vaccine recipients.

Variables		Total No. of recipientsa (n = 376)	Total No. of respondentsa (n = 142)	First dose (n = 77)	Second dose (n = 65)
Age, yr		40 (33–48)	41 (34–48)	40 (34–49)	42 (33–48)
	20–39	183 (48.7)	64 (45.1)	38 (49.4)	26 (40.0)
	40–59	174 (46.3)	75 (52.8)	38 (49.4)	37 (56.9)
	≥ 60	19 (5.1)	3 (2.1)	1 (1.3)	2 (3.1)
Male sex		370 (98.4)	140 (98.6)	76 (98.7)	64 (98.5)
Intradermal administration		365 (97.1)	142 (100)	77 (100)	64 (100)

Data are presented as number (%) or median (interquartile range) unless otherwise indicated.

^aThe total number of JYNNEOS vaccine recipients and respondents to the survey at the National Medical Center during the study period included individuals who received 1 or 2 doses, with the possibility of some individuals being counted redundantly if they received 2 doses.

Overall, 90.9% and 89.2% of individuals experienced at least one adverse reaction of any severity during the 5-day surveillance period following the first and second doses, respectively (Fig. 1). After the first and second doses, 83.1% and 84.6% of the patients, respectively, reported local reactions. Among the local reactions, the most common was pruritus, followed by swelling, redness, and pain. The incidence rates of these reactions after the first dose were 66.2%, 49.4%, 48.1%, and 28.6%, respectively; the corresponding rates after the second dose were 69.2%, 53.8%, 60.0%, and 23.1%. However, these local adverse reactions were mostly mild in severity, and no severe reaction was reported. Systemic adverse reactions were noted in 54.5% and 44.6% of the patients after the first and second doses, respectively. The most common systemic reaction was fatigue, and its incidence rates after the first and second doses were 37.7% and 24.6%, respectively. Although the overall reported rate of systemic reactions was lower than that of local reactions, moderate or severe reactions accounted for a significant proportion of systemic reactions. Regarding unsolicited adverse events, one case each of bruising, skin pigmentation, and dizziness were reported after the first dose. Antipyretic use after immunization was similar after the first and second doses (5.2% and 9.2%, respectively). There were no significant differences in adverse reaction rates between those born in 1979 or earlier and those born after 1979 (Supplementary Tables 1 and 2).

Fig. 1. Local and systemic adverse reactions reported within 5 days after vaccination.

In this active surveillance study, we found that intradermal vaccination with JYNNEOS predominantly induced mild local reactions, while systemic reactions were less frequent and the number of severe symptoms was small. The adverse reaction rates after the first and second doses were comparable. To the best of our knowledge, this is the first study to reveal adverse reactions due to intradermal JYNNEOS vaccination among the target population of the national Mpox vaccination program in South Korea.

A phase II clinical trial that evaluated the safety of intradermal administration of the JYNNEOS vaccine (191 subjects) showed that the most common adverse reaction after intradermal injection was redness at the injection site (99.5%), followed by induration (99.5%), itchiness (89.0%), pain (65.4%), fatigue (51.3%), headache (41.4%), and muscle pain (30.4%).2 The overall reporting rate of adverse events was much higher than that in our study. However, in a real-world study after intradermal JYNNEOS vaccination in Australia, approximately half of the respondents reported local symptoms, and approximately 20% experienced systemic reactions after the first dose. The most common local adverse reactions after the administration of the first and second doses were redness (first dose: 49% and second dose: 30%), pruritis (first dose: 40% and second dose: 26%), and swelling (first dose: 38% and second dose: 22%), while the most common systemic adverse reaction was fatigue (first dose: 18% and second dose: 13%).4 These differences in proportion among studies might have resulted from different study settings, subject characteristics (age group or race), and adverse event reporting systems used in each study. However, fewer respondents reported systemic symptoms than those who reported local reactions, which was consistent among different studies.2,3,4,7

While our study only included intradermal administration of 0.1 mL, we can compare our study with a previous study5 that investigated adverse reactions for 7 days after subcutaneous injection of the standard dose (0.5 mL) of JYNNEOS among over 80 healthcare workers in South Korea. In contrast to intradermal injection, subcutaneous injection was most commonly associated with the following local reactions after the first and second doses: pain (first dose: 66% and second dose: 66%), swelling (first dose: 26% and second dose: 45%), and erythema (first dose: 22.7% and second dose: 44.4%). While solicited local reactions, except pain, were less common with subcutaneous injection, the systemic reactions were comparable to those in our study. However, in previous studies that compared the 2 injection methods, intradermal injection appeared to result in more local reactions.2,4 Since only a fifth dose of the vaccine is administered using the intradermal method for dose-sparing, it might have caused fewer systemic symptoms compared with those caused by subcutaneous injection of the full dose.

Our study has several limitations. Owing to the anonymous nature of the survey in this study, detailed medical information such as underlying diseases was not presented. Also, changes in adverse reactions after the first and second doses of the vaccine could not be investigated. Furthermore, the survey design insufficiently explored unsolicited adverse events. Additionally, this study was conducted at a single hospital, including a small percentage of all vaccine recipients in South Korea, which is insufficient to represent the population.

In conclusion, intradermal administration of the JYNNEOS vaccine appears to be well tolerated, with predominantly mild local adverse reactions among South Koreans.

Ethics statement

This study was approved by the Institutional Review Board of the National Medical Center (IRB nNo. 2023-09-095), which waived the requirement for informed consent from the study participants because of the anonymous nature of the study survey.

SUPPLEMENTARY MATERIALS

Supplementary Data 1

Questionnaire for adverse events after vaccination

Supplementary Table 1

Local and systemic reactions after the first dose of intradermal JYNNEOS vaccination according to the era of the nationwide smallpox vaccination program

Supplementary Table 2

Local and systemic reactions after the second dose of intradermal JYNNEOS vaccination according to the era of the nationwide smallpox vaccination program