Real-world safety data for MVA-BN: Increased frequency of syncope following intradermal administration for immunization against mpox disease.

BACKGROUND: MVA-BN vaccine (Jynneos, Imvamune, Imvanex) was used widely in the 2022 mpox outbreak. This experience provides real-world evidence about the vaccine's safety, particularly regarding intradermal use. METHODS: Bavarian Nordic's global safety database was searched for all adverse events following immunization (AEFIs) with MVA-BN. AEFI numbers were compared among administration routes. Selected events and administered doses were graphed over the mpox outbreak period. RESULTS: A total of 9585 AEFIs have been reported. The rate of myocarditis or pericarditis was <1 per 100,000 doses administered. Eighty-nine cases of syncope, fainting, or loss of consciousness were reported. This number rose after the August 2022 US emergency use authorization for intradermal administration, as did the proportion of all syncope AEFIs reported following intradermal administration (78,7 %). CONCLUSION: Real-world data from large-scale administration of MVA-BN has confirmed the vaccine's established safety profile when administered subcutaneously. Intradermal administration is likely associated with increased syncopal event frequency.

Third-generation smallpox vaccines induce low-level cross-protecting neutralizing antibodies against Monkeypox virus in laboratory workers.

Due to the discontinuation of routine smallpox vaccination after its eradication in 1980, a large part of the human population remains naïve against smallpox and other members of the orthopoxvirus genus. As a part of biosafety personnel protection programs, laboratory workers receive prophylactic vaccinations against diverse infectious agents, including smallpox. Here, we studied the levels of cross-protecting neutralizing antibodies as well as total IgG induced by either first- or third-generation smallpox vaccines against Monkeypox virus, using a clinical isolate from the 2022 outbreak. Serum neutralization tests indicated better overall neutralization capacity after vaccination with first-generation smallpox vaccines, compared to an attenuated third-generation vaccine. Results obtained from total IgG ELISA, however, did not show higher induction of orthopoxvirus-specific IgGs in first-generation vaccine recipients. Taken together, our results indicate a lower level of cross-protecting neutralizing antibodies against Monkeypox virus in recipients of third-generation smallpox vaccine compared to first-generation vaccine recipients, although total IgG levels were comparable.

Summary of the National Advisory Committee on Immunization (NACI) Rapid Response-Interim guidance on the use of Imvamune in the context of monkeypox outbreaks in Canada.

Background: Monkeypox is endemic in Central and West Africa. Cases in non-endemic countries, including Canada, have been increasing since May 2022. Imvamune®, a live, non-replicating smallpox vaccine, was approved by Health Canada for active immunization against smallpox and monkeypox infections and disease in adults determined to be at high risk for exposure. The aim of this interim guidance is to consider the use of Imvamune for post-exposure prophylaxis (PEP) and to summarize the available evidence in support of Imvamune use in this specific current context. Methods: The National Advisory Committee on Immunization (NACI) High Consequence Infectious Disease Working Group (HCID WG) reviewed data on the current status of the monkeypox outbreak, along with additional evidence included in published scientific literature and from manufacturers, regarding the safety, immunogenicity and protection offered by Imvamune. NACI approved these HCID WG recommendations on June 8, 2022. Results: In brief, NACI recommends that PEP, using a single dose of the Imvamune vaccine, may be offered to individuals with high-risk exposures to a probable or confirmed case of monkeypox, or within a setting where transmission is happening. After 28 days, if an individual is assessed as having a predictable ongoing risk of exposure, a second dose may be offered. Imvamune may be offered to special populations; including individuals who are immunosuppressed, pregnant, breastfeeding, younger than 18 years of age and/or with atopic dermatitis. Conclusion: NACI has rapidly developed guidance on the use of Imvamune in Canada in the context of many uncertainties. Recommendations may be revisited as new evidence emerges.

Summary of the National Advisory Committee on Immunization (NACI) Rapid Response: Updated interim guidance on Imvamune in the context of ongoing monkeypox outbreaks.

Background: During the period of monkeypox community transmission and restricted vaccine supply in the summer of 2022, Canadian provinces and territories and a number of vaccine stakeholders indicated the need for consistent national guidance on pre-exposure vaccination (including the identification of priority populations for pre-exposure vaccination programs) and guidance on the potential use of dose-sparing strategies. Methods: The National Advisory Committee on Immunization (NACI) High Consequence Infectious Disease Working Group reviewed data on the status of the monkeypox outbreak along with additional published and non-published evidence regarding the safety, immunogenicity and protection offered by Imvamune®. NACI approved updated recommendations on September 16, 2022, and on September 23, 2022 it released updated interim guidance on the use of Imvamune in the context of the ongoing monkeypox outbreak. Results: During periods of adequate vaccine supply, NACI recommended that Imvamune pre-exposure vaccination should be offered as a two-dose primary series, with at least 28 days between the two sub-cutaneous doses. When supply is limited, guidance was provided for the use of dose sparing strategies, including extended dosing intervals and fractional intradermal dosing to maximize vaccine coverage for those at highest risk of exposure to the monkeypox virus. Conclusion: The updated NACI recommendations provide additional guidance on the use of Imvamune for the management of the 2022 monkeypox outbreak in Canada and may be considered to maximize vaccine coverage in outbreak settings when supply is limited.

Vaccinating against monkeypox in the Democratic Republic of the Congo.

Healthcare-associated transmission of monkeypox has been observed on multiple occasions in areas where the disease is endemic. Data collected by the US Centers for Disease Control and Prevention (CDC) from an ongoing CDC-supported program of enhanced surveillance in the Tshuapa Province of the Democratic Republic of the Congo, where the annual incidence of human monkeypox is estimated to be 3.5-5/10,000, suggests that there is approximately one healthcare worker infection for every 100 confirmed monkeypox cases. Herein, we describe a study that commenced in February 2017, the intent of which is to evaluate the effectiveness, immunogenicity, and safety of a third-generation smallpox vaccine, IMVAMUNE®, in healthcare personnel at risk of monkeypox virus (MPXV) infection. We describe procedures for documenting exposures to monkeypox virus infection in study participants, and outline lessons learned that may be of relevance for studies of other investigational medical countermeasures in hard to reach, under-resourced populations.

Repeated high-dose (5 × 10(8) TCID50) toxicity study of a third generation smallpox vaccine (IMVAMUNE) in New Zealand white rabbits.

Concern over the release of variola virus as an agent of bioterrorism remains high and a rapid vaccination regimen is desirable for use in the event of a confirmed release of virus. A single, high-dose (5×10(8) TCID50) of Bavarian Nordic's IMVAMUNE was tested in a Phase-II clinical trial, in humans, as a substitute for the standard (1×10(8) TCID50), using a 2-dose, 28-days apart regimen. Prior to this clinical trial taking place a Good Laboratory Practice, repeated high-dose, toxicology study was performed using IMVAMUNE, in New Zealand white rabbits and the results are reported here. Male and female rabbits were dosed twice, subcutaneously, with 5×10(8) TCID50 of IMVAMUNE (test) or saline (control), 7-days apart. The clinical condition, body-weight, food consumption, haematology, blood chemistry, immunogenicity, organ-weight, and macroscopic and microscopic pathology were investigated. Haematological investigations indicated changes within the white blood cell profile that were attributed to treatment with IMVAMUNE; these comprised slight increases in neutrophil and monocyte numbers, on study days 1-3 and a marginal increase in lymphocyte numbers on day 10. Macroscopic pathology revealed reddening at the sites of administration and thickened skin in IMVAMUNE, treated animals. After the second dose of IMVAMUNE 9/10 rabbits seroconverted, as detected by antibody ELISA on day 10, by day 21, 10/10 rabbits seroconverted. Treatment-related changes were not detected in other parameters. In conclusion, the subcutaneous injection of 2 high-doses of IMVAMUNE, to rabbits, was well tolerated producing only minor changes at the site of administration. Vaccinia-specific antibodies were raised in IMVAMUNE-vaccinated rabbits only.

Sex difference in immune response to vaccination: A participant-level meta-analysis of randomized trials of IMVAMUNE smallpox vaccine.

INTRODUCTION: Previous research shows immune response to vaccination differs by sex but this has not been explored for IMVAMUNE, a replication-deficient smallpox vaccine developed in response to the potential for bioterrorism using smallpox. METHODS: We conducted a participant-level meta-analysis (N=275, 136 men, 139 women) of 3 randomized trials of IMVAMUNE conducted at 13 centers in the US through a federally-funded extramural research program. Studies were eligible for inclusion if they tested the standard dose (1×10(8)TCID50/mL on Days 0 and 28) of liquid formulation IMVAMUNE, were completed at the time of our search, and enrolled healthy vaccinia-naïve participants. Models of the peak log2 ELISA and PRNT titers post-second vaccination were constructed for each study with sex as a covariate. Results from these models were combined into random effects meta-analyses of the sex difference in response to IMVAMUNE. We then compared this approach with fixed effects models using the combined participant level data. RESULTS: In each study the mean peak log2 ELISA titer was higher in men than women but no single study demonstrated a statistically significant difference. Combination of the adjusted study-specific estimates into the random effects model showed a higher mean peak log2-titer in men compared with women (absolute difference [men-women]: 0.32, 95% CI: 0.02-0.60). Fixed effects models controlling for study showed a similar result (log2 ELISA titer, men-women: 0.34, 95% CI: 0.04-0.63). This equates to a geometric mean peak titer that is approximately 27% higher in men than women (95% CI: 3-55%). Peak log2 PRNT titers were also higher (although not significantly) in men (men-women: 0.14, 95% CI: -0.30 to 0.58). CONCLUSION: Our results show statistically significant differences in response to IMVAMUNE comparing healthy, vaccinia-naïve men with women and suggest that sex should be considered in further development and deployment of IMVAMUNE and other MVA-based vaccines.

Comparison of lyophilized versus liquid modified vaccinia Ankara (MVA) formulations and subcutaneous versus intradermal routes of administration in healthy vaccinia-naïve subjects.

BACKGROUND: Modified vaccinia Ankara (MVA) is being developed as a safer smallpox vaccine and is being placed in the US Strategic National Stockpile (SNS) as a liquid formulation for subcutaneous (SC) administration at a dose of 1×10(8) TCID50 in a volume of 0.5mL. This study compared the safety and immunogenicity of the standard formulation, dose and route with both a more stable, lyophilized formulation and with an antigen-sparing intradermal (ID) route of administration. METHODS: 524 subjects were randomized to receive either a full dose of Lyophilized-SC, a full dose of Liquid-SC or 20% (2×10(7) TCID50 in 0.1mL) of a full dose Liquid-ID MVA on Days 0 and 28. Safety and immunogenicity were followed through 180 days post second vaccination. RESULTS: Among the 3 groups, the proportion of subjects with moderate/severe functional local reactions was significantly different (P=0.0013) between the Lyophilized-SC group (30.3%), the Liquid-SC group (13.8%) and Liquid-ID group (22.0%) only after first vaccination; and for moderate/severe measured erythema and/or induration after any vaccination (P=0.0001) between the Lyophilized-SC group (58.2%), the Liquid-SC group (58.1%) and the Liquid-ID group (94.8%) and the reactions lasted longer in the Liquid-ID group. In the ID Group, 36.1% of subjects had mild injection site skin discoloration lasting ≥6 months. After second vaccination Day (42-208), geometric mean of peak neutralization titers were 87.8, 49.5 and 59.5 for the Lyophilized-SC, Liquid-SC and Liquid-ID groups, respectively, and the maximum number of responders based on peak titer in each group was 142/145 (97.9%), 142/149 (95.3%) and 138/146 (94.5%), respectively. At 180 days after the second vaccination, geometric mean neutralization titers declined to 11.7, 10.2 and 10.4 with only 54.3%, 39.2% and 35.2% of subjects remaining seropositive for the Lyophilized-SC, Liquid-SC and Liquid-ID groups, respectively. Both the Lyophilized-SC and Liquid-ID groups were considered non-inferior (primary objective) to the Liquid-SC group. CONCLUSIONS: Transitioning to a lyophilized formulation, which has a longer shelf life, will not negatively impact immunogenicity. In a situation where insufficient vaccine is available, ID vaccination could be used, increasing the number of available doses of vaccine in the SNS 5-fold (i.e., from 20 million to 100 million doses).

Phase II randomized, double-blinded comparison of a single high dose (5×10(8) TCID50) of modified vaccinia Ankara compared to a standard dose (1×10(8) TCID50) in healthy vaccinia-naïve individuals.

INTRODUCTION: Reintroduction of Variola major as an agent of bioterrorism remains a concern. Time to seroconversion and plaque reduction neutralizing antibody titers (PRNT) of 1 or 2 standard doses (SD) were compared to a single high dose (HD) of modified vaccinia Ankara (MVA). METHODS: Ninety subjects were randomized 1:1 to receive 1 HD or 2 SD of MVA subcutaneously on Days 0 and 28 in a placebo-controlled trial. Serum was collected for PRNT and ELISA. Subjects were followed for safety for the entire study. RESULTS: The HD was well-tolerated. Using Bavarian Nordic's ELISA, subjects in both groups achieved seroconversion by Study Day 15 (HD) and Day 28 (SD). Before second vaccination, the hazard rate of seroconverting for the HD group was 1.7 times the SD group with a median time for seroconversion of 14 days for both groups. The peak titer of one HD vaccine was superior to one dose of SD vaccine but inferior to the peak titer after the second dose of the SD vaccination regimen. Using Saint Louis University's PRNT, peak titers were 95.8 and 65.2 for the HD and SD groups, respectively, prior to second vaccination. Non-inferiority of the SD group was not established. The proportions of positives were 93.3% (42/45) and 82.2% (37/45) for the HD and SD groups, respectively. The peak titer after two standard doses was superior to that of the HD. CONCLUSIONS: HD MVA was safe and well-tolerated. While the hazard rate for seroconverting was significantly higher in the HD group before second dose, the effect was small as the median time to seroconversion was identical. When comparing PRNT, non-inferiority of one SD was not established and the peak titers were low for both groups. The HD peak response was inferior to the standard two-dose regimen response based on ELISA and PRNT.