Source: Health Products and Food Branch (CA) Revision Year: 2022
IMVAMUNE is a live, attenuated, and non-replicating viral vaccine produced from the orthopoxvirus strain Modified Vaccinia Ankara-Bavarian Nordic (MVA-BN) (see Section 13 – Product Characteristics).
Clinical and pre-clinical studies have shown that both humoral and cellular immune responses induced with IMVAMUNE in animal species (i.e. mice and monkeys) and human individuals vaccinated with IMVAMUNE are comparable to immune responses induced by replicating smallpox vaccines used to eradicate smallpox (see Section 10.2). Furthermore, animal model challenge studies performed in mice and monkeys have shown that IMVAMUNE confers protection against orthopoxvirus infections including monkeypox and vaccinia infections.
A direct comparison of IMVAMUNE-elicited immune responses (ELISA and PRNT) in humans to those elicited by a licensed smallpox vaccine (e.g. Dryvax or ACAM2000) provided a means of inferring efficacy, taking into account comparative ELISA and PRNT responses in animal challenge studies. These lethal animal challenge studies in two species have shown protection in mice and NHP while using a replicating licensed smallpox vaccine (e.g. Dryvax or ACAM2000) as a comparator. Additional immunogenicity data generated on human specimens provide further support of clinical efficacy as follows:
The ability of IMVAMUNE to boost a pre-existing immunity in vaccinia-experienced subjects (ELISA and PRNT) can be seen as supporting clinical efficacy, as demonstrated for ACAM2000. Boosting an immune response in subjects previously vaccinated with a smallpox vaccine with a proven efficacy was evidence that ACAM2000 is capable of providing protection against smallpox in this population. The same effect has been demonstrated for IMVAMUNE in two large clinical Phase II trials (POX-MVA005 and POX-MVA-011) that enrolled vaccinia-experienced subjects: IMVAMUNE provided a strong recall response (ELISA and PRNT) in healthy and HIV infected subjects previously vaccinated with a smallpox vaccine of proven efficacy against smallpox.
A single dose of IMVAMUNE in vaccinia-naive subjects induces a long-lived B cell memory that can be boosted to the same antibody levels as in subjects vaccinated according to the standard schedule (two IMVAMUNE doses): 2 years after priming with either one or two doses of IMVAMUNE, the recall response (ELISA and PRNT) to a single booster dose of IMVAMUNE is rapid (within 7 days), stronger compared to the primary responses (>2.5-fold), and comparable to that observed in individuals previously vaccinated with a licensed smallpox vaccine with proven efficacy (POX-MVA023).
A Phase I study (POX-MVA-002) performed at a time when Dryvax was still licensed in the US and permitted for use in clinical trials demonstrated that the peak and long-term immune responses (ELISA and PRNT) induced by IMVAMUNE were comparable to those induced by Dryvax in healthy vaccinia-naïve subjects.
In the same Phase I study, prior vaccination of healthy, vaccinia-naïve subjects with two doses of IMVAMUNE prevented or attenuated the vaccine take following a subsequent vaccination with Dryvax as judged by either the absence of or a significant reduction in redness/swelling, healing time and VV titers in the skin pustule. The prevention and/or attenuation of the Dryvax lesion has historically been associated with pre-existing immunity against smallpox infections, acquired either by previous vaccination(s) using conventional smallpox vaccines or a prior smallpox infection.
IMVAMUNE induced comparable variola virus neutralizing titers compared to subjects vaccinated with Dryvax. In vitro evaluation of the peak response sera obtained from study POX-MVA-002 demonstrated that the immune response elicited by IMVAMUNE, measured by the ability to neutralize variola virus in a PRNT, was comparable to that elicited by Dryvax. In addition, 90% neutralization at serum dilutions > 1:160 was only observed with IMVAMUNE and not with Dryvax. The responses generated using the variola-specific PRNT were highly correlated to results generated using the BN ELISA and vaccinia-specific PRNT.
A retrospective study demonstrated non-inferiority of total (ELISA) and neutralizing (PRNT) antibodies induced in healthy vaccinia-naïve subjects after vaccination with IMVAMUNE drawn from 3 BN clinical studies (POX-MVA-005, POX-MVA-008 and POX-MVA-011). Responses from these 3 clinical studies were compared to responses obtained from 5 National Institutes of Health/Division of Microbiology and Infectious Diseases (NIH/DMID) sponsored studies with Dryvax/Wetvax.
In a Phase III study (POX-MVA-013) consistency of three consecutively produced MVABN lots was proven in terms of humoral immunogenicity (PRNT GMT equivalence).
In 20 completed clinical trials, IMVAMUNE has demonstrated the ability to induce a fast and strong, vaccinia-specific immune response. Included are healthy vaccinia-naïve and vaccinia-experienced populations as well as populations that are contraindicated to receive replicating smallpox vaccines, such as HIV-1 infected and AD subjects. The immunogenicity endpoints of these studies (seroconversion rates and GMTs by ELISA and PRNT) were based on historical (epidemiological and immunological) evidence that a measurable immune response against orthopoxviruses is correlated with the appearance of a take and/or protection and therefore likely to predict clinical benefit.
A Phase III study demonstrated that IMVAMUNE elicited peak antibody responses (based on PRNT and ELISA GMTs) that were non-inferior to those elicited by the US licensed replicating smallpox vaccine ACAM2000, which are considered protective, in healthy, vaccinia-naïve subjects (POX-MVA-006).
Prior vaccination with two doses of IMVAMUNE before ACAM2000 scarification compared with ACAM2000 scarification alone attenuated the take as judged by a significant reduction in lesion area and diameter and accelerated lesion healing time. This shows that IMVAMUNE is able to suppress the viral replication induced by ACAM2000, providing evidence of the efficacy afforded by IMVAMUNE to protect against smallpox.
Data on long-term immunogenicity covering a period of 24 months following primary vaccination with IMVAMUNE are currently available. Although antibody titers tend to decrease to low levels two years after priming, these can be readily boosted following a single booster dose of IMVAMUNE to even higher peak GMT responses (ELISA and PRNT) compared to the primary response. Repeated exposure to IMVAMUNE (booster vaccination) increases the antibody titers (3.4-fold higher GMTs by ELISA and 2.7-fold higher GMT by PRNT) compared to the priming vaccination (see CLINICAL TRIALS, Study Results POX-MVA-005 and POX-MVA-023).
There is limited data on long-term immunogenicity following a booster dose in vacciniaexperienced and in IMVAMUNE-experienced, healthy subjects. However, two weeks after a single booster dose, even higher antibody titers (ELISA and PRNT) are observed than after priming. Assuming a similar decline of antibody titers as in the primed population, data suggests that a booster dose every two years is sufficient in vaccinia-experienced and in IMVAMUNEexperienced, healthy subjects (see CLINICAL TRIALS, Study Results POX-MVA-023).
Please refer to Section 7.1.
Due to the absence of naturally occurring smallpox, the clinical efficacy of a smallpox vaccine cannot be directly demonstrated in humans, since it is not feasible and would not be ethical to expose people to an artificial smallpox infection (challenge). Therefore, clinical efficacy was inferred from nonclinical studies using animal challenge models (Section 16.1 and Section 10.2)
as well as in clinical studies where immune responses induced by IMVAMUNE and by licensed smallpox vaccines were compared (Section 16.2).
The pharmacodynamic properties of IMVAMUNE were assessed in mice and non-human primates (NHP). Variola, the causative agent of smallpox in humans, belongs to the orthopox family of viruses, which includes a number of closely related poxviruses e.g. mousepox virus (ectromelia virus [ECTV]), cowpox virus, monkeypox virus (MPXV) and vaccinia virus (VV). It has been well established that exposure to one of the poxviruses provides protection from some of the other orthopox family members and indeed, smallpox has been eradicated by a worldwide vaccination campaign using various VV strains e.g. Lister-Elstree or New York City Board of Healthy (e.g. Dryvax).
Animal efficacy data have been generated in four separate animal models that have been specifically developed to demonstrate the efficacy of IMVAMUNE in comparison to replicating smallpox vaccines.
NHP studies using either a systemic (i.v.) or respiratory (i.t.) lethal challenge with MPXV have demonstrated:
Two murine models that utilize a lethal intranasal (i.n.) challenge with either VV Western Reserve (WR) or ECTV that closely mimic smallpox infection in humans were used to test vaccine efficacy. Findings from these studies demonstrated the following:
The toxicity of IMVAMUNE was evaluated in repeated dose studies in rats and rabbits. Embryofetal development studies (segment II) were performed in rats and rabbits, and a peri- and postnatal development toxicity study (segment III) was performed in rats. The local tolerance of IMVAMUNE was evaluated as part of the repeat-dose toxicity studies.
Table 10. Toxicology Studies Overview:
| Type of Study | Species | Route of Administration | Dosing level (Inf.U) | Schedule/Duration |
|---|---|---|---|---|
| Repeat-dose toxicity | Rats / Crl:CD (SD) | Subcutaneous | 4.9 × 108 | 4 applications within 22 days |
| Rabbits / New Zealand White | Subcutaneous | 4.9 × 108 | 2 applications at 8 days interval | |
| Rabbits / New Zealand White | Subcutaneous | 1 × 107, 1 × 108 | 3 applications within 42 days | |
| Rabbits / New Zealand White | Subcutaneous | 1 × 107, 1 × 108 | 3 applications within 42 days | |
| Reproductive and develop-mental toxicity | Rats / Crl(Wi)BR- Wistar | Subcutaneous | 1 × 107, 1 × 108 | 2 immunizations at 2 weeks interval |
| Rabbits / New Zealand White | Subcutaneous | 1 × 107, 1 × 108 | 3 immunizations at 2 weeks interval | |
| Rats / Crl:(Wi)BR- Wistar | Subcutaneous | 1 × 107, 1 × 108 | 3 immunizations at 2 weeks interval |
IMVAMUNE did not cause any life-threatening toxicity and there were no adverse changes in observed clinical signs, ophthalmology, clinical chemistry, urinalyses, gross tissue evaluation, organ weights or histopathologic tissue evaluation indicative of direct target organ toxicity when administered to rats and rabbits at doses up to 4.9 × 108 Inf.U applied up to 4 times within a period of 42 days. The dose of 4.9 × 108 Inf.U is approximately 5 times the dose (in absolute terms) and 20 – 200 times the dose (based on mg/kg) to be used in humans (i.e. 1 × 108 Inf.U of IMVAMUNE; two-dose vaccination regimen).
Haematological parameters did not provide any evidence for immunotoxic effects.
Local tolerance was evaluated in biodistribution studies as well as in the repeat-dose toxicity studies. The only reported clinical observations were swelling and red discoloration at the injection site.
In development toxicity studies, IMVAMUNE (up to 1 × 108 Inf.U; highest tested dose) had no adverse effect on gestation, lactation and maternal behaviour in female dams and on the behavioural/functional development of the offspring (F1 generation) of treated female rats and rabbits. No adverse effects on embryo-fetal development were observed when dosing IMVAMUNE 14 days prior to the day of sperm positivity (Day –14) and on the day of sperm positivity (Day 0) in rats and at 14 days prior to the day of sperm positivity (Day –14), on the day of sperm positivity (gestation Day 0), and on gestation Day 14 in rabbits. Vaccination with IMVAMUNE yielded a robust, dose dependent antibody response in dams and conferred passive immunity to their litters, confirming this species as relevant animal model for toxicity testing. Overall, nonclinical studies provided no evidence of perinatal toxicity or teratogenicity IMVAMUNE.
No specific juvenile animal studies were performed.
The toxicity study results demonstrate that IMVAMUNE induces reversible and vaccine expected side effects.
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