NACI Rapid Response: Interim guidance on the use of Imvamune® in the context of monkeypox outbreaks in Canada

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Organization: Public Health Agency of Canada

Published: 2022-08-03

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Preamble

The National Advisory Committee on Immunization (NACI) is an External Advisory Body that provides the Public Health Agency of Canada (PHAC) with independent, ongoing and timely medical, scientific, and public health advice in response to questions from PHAC relating to immunization.

In addition to burden of disease and vaccine characteristics, PHAC has expanded the mandate of NACI to include the systematic consideration of programmatic factors in developing evidence based recommendations to facilitate timely decision-making for publicly funded vaccine programs at provincial and territorial levels.

The additional factors to be systematically considered by NACI include: economics, ethics, equity, feasibility, and acceptability. Not all NACI statements will require in-depth analyses of all programmatic factors. While systematic consideration of programmatic factors will be conducted using evidence-informed tools to identify distinct issues that could impact decision-making for recommendation development, only distinct issues identified as being specific to the vaccine or vaccine-preventable disease will be included.

This statement contains NACI's independent advice and recommendations, which are based upon the best current available scientific knowledge. This document is being disseminated for information purposes. People administering the vaccine should also be aware of the contents of the relevant product monograph. Recommendations for use and other information set out herein may differ from that set out in the product monographs of the Canadian manufacturers of the vaccines. Manufacturer(s) have sought approval of the vaccines and provided evidence as to its safety and efficacy only when it is used in accordance with the product monographs. NACI members and liaison members conduct themselves within the context of PHAC's Policy on Conflict of Interest, including yearly declaration of potential conflict of interest.

Background

Monkeypox virus is a member of the Orthopoxvirus genus, which also includes variola virus (smallpox virus), vaccinia virus, cowpox, and other poxviruses. Monkeypox viruses are zoonotic, therefore infection may occur in contexts where there is contact with wild species that are susceptible to monkeypox viruses. Human-to-human transmission of monkeypox virus also occurs amongst close contacts of people infected with monkeypox. Monkeypox is endemic in Central and West Africa, but there have been cases and outbreaks in non-endemic countries due to international travel or the importation of infected animals from affected areas. There are two distinct clades of monkeypox virus: the Congo Basin (Central African) clade and the West African clade. The Congo Basin clade has caused more severe illness.

Based on historical data, monkeypox has a typical incubation period of 6-13 days from exposure but can range from 5-21 days Footnote 1. The disease is usually self-limiting and resolves within 14 to 28 days. Symptoms include fever, headache, back pain, myalgia, asthenia, lymphadenopathy and skin lesions/rash which typically tend to be more concentrated on the face, extremities, and oral mucous membranes, but can also appear in the genital area. Rash lesions begin as macules and further develop to papules, vesicles, pustules, and then form crusts. The duration of communicability for monkeypox virus may be up to 2-4 weeks, based on limited evidence of PCR detection of monkeypox in the upper respiratory tract Footnote 2. Potential complications of monkeypox include secondary bacterial infections, pneumonia, sepsis, encephalitis, and vision loss from corneal inflammation. Monkeypox virus may cause severe disease in young children, individuals who are immunocompromised Footnote 3, and those who are pregnant. Information about monkeypox in people who are pregnant is sparse but cases of first trimester miscarriage and stillbirths have been reported Footnote 4.

In the current 2022 multi-country outbreak, monkeypox cases may have an atypical presentation including oral, genital, and/or anal lesions with or without fever, or systemic symptoms. Person-to-person transmission can occur through direct contact with a person who is infected, including intimate sexual activity, or through shared contaminated objects. The potential for respiratory transmission is unknown at this time but may also be possible.

The 2022 multi-country monkeypox outbreak represents the first incidence of broader community transmission in a number of countries outside of certain regions of Africa. Initial detection in early May 2022 was a family cluster of three cases in the United Kingdom, with one case having recent travel history to an endemic region. On May 15, the World Health Organization (WHO) was notified of four additional confirmed cases, unlinked to travel, and this suggested more extensive community transmission of the virus. Since then, additional cases have been reported in the United Kingdom and internationally, including Canada. By June 7, at least 1,060 confirmed cases from 30 non-endemic countries and territories have been reported in official and media sources according to monitoring by the Global Public Health Intelligence Network (GPHIN). Ten countries have reported at least 10 confirmed cases (the United Kingdom [302], Spain [210], Portugal [166], Canada [81], Germany [80], France [51], the Netherlands [40], the United States [31], Italy [20], and Belgium [17]).

As of June 7, 81 cases of monkeypox had been confirmed in Canada (71 in Quebec, 8 in Ontario, 1 in Alberta, and 1 in British Columbia). According to open-source information, the Quebec cases are mainly men between 30-55 years of age, and they presented to Sexually Transmitted and Blood-Borne Infection clinics in the Montreal area. The infections were suspected to have been acquired in Montreal. Some of the individuals with infection reported links to travel in Belgium and Mexico.

Smallpox vaccines used during the global smallpox eradication programs may provide some protection against monkeypox Footnote 1. However, global smallpox vaccination programs ended in 1980 when smallpox was declared eradicated. Discontinuation of smallpox vaccination for travel was recommended by the WHO in 1980 and was no longer required by any country by 1982. Canadians born in 1972 or later have not been routinely immunized against smallpox (unless immunized for other purposes such as travel or work-related risks). For those who have been previously vaccinated for smallpox (i.e., eligible for vaccine in 1980 or earlier), the degree of protection conferred from the smallpox vaccine against monkeypox infection may be up to 85% Footnote 5, however the durability of protection and the degree of protection against the current strain of monkeypox remains unknown.

Objective

In the context of the rapidly evolving multi-country monkeypox outbreak, this rapid response was undertaken to provide guidance on the use of an orthopoxvirus (Imvamune®) vaccine with potential efficacy against monkeypox. Imvamune® is stockpiled within Canada's National Emergency Strategic Stockpile for the purposes of national security due to its potential efficacy against variola, the virus that causes smallpox. Due to the unique epidemiology and supply considerations, the planned task for this rapid response was to consider the use of Imvamune® for post-exposure prophylaxis and to summarize the available evidence in support of Imvamune® use in this specific current context.

Unrelated to the current monkeypox outbreak, NACI was also asked to consider use of Imvamune® in laboratory research settings where replicating orthopoxviruses are studied.

NACI and PHAC continue to monitor the evolving scientific data recognizing that the trajectory of the current monkeypox outbreak remains unclear, the situation is rapidly evolving and there may be additional considerations in the coming weeks.

Methods

On May 26 and May 27, 2022, monkeypox data were discussed and reviewed by the NACI High Consequence Infectious Disease working group (HCID WG), along with input from the Public Health Ethics Consultative Group (PHECG), Canadian Immunization Committee (CIC), NACI's Vaccine Safety Working Group (VSWG) and two LGBTQ2S+ groups from Ontario and BC. The HCID WG reviewed data on the current status of the monkeypox outbreak, along with additional evidence included in published scientific literature and from the manufacturer, regarding the safety, immunogenicity and protection offered by Imvamune®. NACI approved these HCID WG recommendations on June 8, 2022.

Vaccine

Imvamune® (also called Modified Vaccinia Ankara-Bavarian Nordic (MVA-BN), Jynneos®, Imvanex®) is a non-replicating, third-generation smallpox vaccine manufactured by Bavarian Nordic. Imvamune® was initially authorized for use in Canada on November 21, 2013, as an Extraordinary Use New Drug Submission (EUNDS) for use by the Canadian Government in an emergency situation for active immunization against smallpox infection and disease in persons 18 years of age and older who have a contraindication to the first or second generation smallpox vaccines. It was subsequently approved under a supplement to the EUNDS on November 5, 2020 for active immunization against smallpox, monkeypox and related Orthopoxvirus infections and disease in adults 18 years of age and older determined to be at high risk for exposure Footnote 6.

Imvamune® contains trace amounts of host cell DNA and protein, benzonase, ciprofloxacin and gentamicin. No preservative or adjuvant is added to the formulation. The MVA virus is also being developed as a vector vaccine platform against other viruses, including tuberculosis, respiratory syncytial virus, Ebola virus and others.

Imvamune® differs from previous generations of smallpox vaccines as it is a non-replicating vaccine virus in humans, meaning based on preclinical studies, it is not able to produce more copies of itself Footnote 7. While Imvamune® is capable of replicating to high titers in avian cell lines such as chicken embryo fibroblasts, it is attenuated and has limited replication capability in human cells Footnote 8.

Preclinical data from previous generation smallpox vaccines showed decreased immune responses when tecovirimat (TPOXX, an antiviral drug from SIGA technologies) was administered concurrently with earlier generation smallpox vaccines Footnote 9. Due to the differences between previous generation smallpox vaccines and Imvamune®, it is unclear if antivirals could impact protection offered by Imvamune®.

Table 1. Use and overview of key features of IMVAMUNE® vaccine according to product monograph
Product brand name and formulation IMVAMUNE®
Smallpox and Monkeypox Vaccine
Type of vaccine Modified Vaccinia Ankara-Bavarian Nordic®
(live-attenuated, non-replicating)
Date of authorization in Canada Date of Initial Approval: November 21, 2013
Date of authorization for Monkeypox as expanded indication: November 5, 2020
Date of latest Revision: November 26, 2021
Authorized ages for use Adults 18 years of age and older
Authorized dose and schedule Primary Series: Two doses of 0.5 mL (0.5 x 108 Infectious units), 28 days apart
Booster dose (2 years after primary series): One dose of 0.5 mL (0.5 x 108 Inf.U)
Potential allergens Traces of residual host (egg) cell DNA and proteinFootnote a
tromethamineFootnote b (trometamol, tris)
benzonaseFootnote c
gentamicin and ciprofloxacinFootnote d
Adjuvant / Preservatives The vaccine contains no adjuvant or preservatives
Contraindications
  • Patients who are hypersensitive to this vaccine or to any ingredient in the formulation or component of the container.
  • Individuals who show hypersensitivity reactions after receiving the first dose of the vaccine should not be given the second dose.
  • As with other vaccines, vaccination with IMVAMUNE® must be postponed in persons with acute febrile conditions if used for non-emergency (pre-event) prophylaxis.
Storage
  • Store frozen at -20°C ± 5°C or -50°C ±10°C or -80°C ±10°C.
  • After thawing, the vaccine should be used immediately or can be stored at 2°C –8°C for up to 2 weeks prior to use.
  • Do not refreeze a vial once it has been thawed.
  • Protect from light.
Handling
  • Thaw at room temperature. The drug product should appear as a pale milky colored homogeneous suspension.
  • The single-dose vial should be swirled gently (not shaken) for at least 30 seconds to ensure homogeneity upon thawing,
  • The vaccine must not be used if any foreign particulate matter are visible.
Reconstitution No
Route of administration 0.5 mL subcutaneous injection, at any site
Syringe and needle selection
  • Withdraw with a syringe and needle long enough to reach the bottom of the vial.
  • For injection, needle should be changed to a subcutaneous injection needle
Table 1 Footnote a

In Canada, there are several vaccines manufactured by processes involving hens' eggs or their derivatives, such as chicken cell cultures

Table 1 Return to footnote a referrer

Table 1 Footnote b

Tromethamine (trometamol, Tris) may very rarely cause allergic reactions and is found in some medications injected to do tests (contrast media) as well as other medications taken by mouth or injection, and some creams and lotions. Note that this is not a complete list.

Table 1 Return to footnote b referrer

Table 1 Footnote c

Benzonase is used for purification of viral vaccines, viral vectors for vaccine, cell and gene therapy, and oncolytic viruses, removing DNA/RNA from proteins and other biologicals; reduction of viscosity caused by nucleic acids; sample preparation in electrophoresis and chromatography and prevention of cell clumping.

Table 1 Return to footnote c referrer

Table 1 Footnote d

Gentamicin and ciprofloxacin are used as antibiotics in the treatment of some bacterial infections.

Table 1 Return to footnote d referrer

Recommendations

Please see Table 2 for an explanation of strong versus discretionary NACI recommendations. Please see Appendix A which summarizes the clinical and preclinical data for Imvamune®.

For those without a contraindication to the vaccine:

1. NACI recommendation for the use of Imvamune® as Post-Exposure Prophylaxis (PEP) in adults:

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. PEP should be offered as soon as possible and within 4 days of last exposure and can be considered up to 14 days of last exposure. PEP should not be offered to individuals who are symptomatic and who meet the definition of suspect, probable or confirmed case.

After 28 days, if an individual is assessed as having a predictable ongoing risk of exposure, a second dose may be offered. A second dose should not be offered to individuals who are symptomatic and therefore after medical evaluation meet suspect, probable or confirmed monkeypox case definitions.

For individuals who had received a live replicating 1st or 2nd generation smallpox vaccine in the past and who sustain a high risk exposure to a probable or confirmed case of monkeypox, a single dose of Imvamune® PEP may be offered (i.e. as a booster dose).

The benefit of protection against infection should be discussed with a healthcare provider and weighed against the potential risk of recurrent myocarditis for individuals with a history of myocarditis/pericarditis linked to a previous dose of live replicating 1st and 2nd generation smallpox vaccine and/or Imvamune®; a precautionary approach is warranted at this time until more information is available.

(Discretionary NACI Recommendation)

*High risk exposures: to be defined by the Public Health Agency of Canada.

Individuals with high-risk exposures to people infected with monkeypox may derive maximum benefit from PEP if offered very soon after such exposure. However some high-risk exposures may extend beyond 28 days. In situations where confirmed high risk exposures are multiple (i.e., beyond a single case) and expected to be ongoing over a period of weeks, PEP recipients may be offered a second dose 28 days after the first dose.

2. NACI recommendation for Pre-Exposure Prophylaxis (PrEP) for adults at high risk of occupational exposure in a laboratory research setting:

NACI recommends that Imvamune® PrEP may be offered to personnel working with replicating orthopoxviruses that pose a risk to human health (vaccinia or monkeypox) in laboratory settings and who are at high risk of occupational exposure. If Imvamune® is used, two doses should be given at least 28 days apart. A booster dose may be offered after 2 years if the risk of exposure extends beyond that time. This recommendation does not apply to clinical diagnostic laboratory settings at this time, due to very low risk of transmission.

For immunocompetent individuals who have received a live replicating 1st or 2nd generation smallpox vaccine in the past and who are at high risk for occupational exposure, a single dose of Imvamune® may be offered (i.e. as a booster dose), rather than the two dose primary vaccine series. This single Imvamune® dose should be given at least two years after the latest live replicating smallpox vaccine dose.

In consultation with a physician, the benefit of protection against infection should be weighed against the risk of recurrent myocarditis for individuals with a history of myocarditis/pericarditis linked to a previous dose of live replicating 1st and 2nd generation smallpox vaccine and/or Imvamune®; a precautionary approach is warranted at this time until more information is available.

(Discretionary NACI Recommendation)

Laboratory workers may be at heightened risk for of occupational exposure to replicating orthopoxviruses when working in a research laboratory context. Orthopoxviruses that pose a risk to human health include vaccinia and monkeypox. Variola virus (the causative agent of smallpox) was declared eradicated in 1980. Laboratory workers handling orthopoxviruses that do not put human health at risk, including those that cause disease only in animals or orthopoxviruses that are unable to replicate (including Modified Vaccinia Ankara) should not be offered PrEP. In addition, laboratory workers who work outside of a research laboratory setting, including diagnostic laboratory or specimen transport workers, and people working in clinical health care settings should not be offered PrEP.

3. NACI recommendation for Special Populations:

NACI recommends that Imvamune® vaccine may be offered to the following populations, if recommended to receive vaccine based on exposure risk:

(Discretionary NACI Recommendation)

Immunocompromised populations (including people living with HIV) may particularly benefit from vaccination as these populations may be at risk for more severe outcomes if infected depending on the nature and degree of the immunosuppression. Although data on the use of Imvamune®in immunocompromised populations are limited, Imvamune®has been tested clinically in people living with HIV (CD4 ≥100 cells/µL) and hematopoietic stem transplant patients (studied two years post-HSCT) and safety was comparable to healthy controls in these populations. There are limited data overall on VE/immunogenicity or safety in immunocompromised populations, but immunosuppression increases risk of negative outcomes due to infection. Live vaccines are usually contraindicated for immunocompromised populations; however, Imvamune® may be safely used in this group as it is considered a non-replicating vaccine Footnote 8. When using Imvamune® as PrEP in immunocompromised individuals, 2 doses are recommended regardless of previous smallpox vaccine history.

If at risk for infection, pregnant populations may particularly benefit from vaccination as these populations may be at risk for severe outcomes from disease. Imvamune® has never been tested in persons who are pregnant. Though limited, safety and toxicity studies have identified no concerning safety signals. There is a lack of evidence of safety and efficacy of Imvamune® PEP or PrEP in this group, though at this time there is no reason to believe that vaccination would have any adverse impact on the person who is pregnant or the fetus. Live vaccines are usually contraindicated for pregnant populations; however, Imvamune® may be used in this group as it is considered a non-replicating vaccine. The risks due to monkeypox infection should be weighed against the lack of evidence of vaccine safety.

Lactating populations are not at higher risk for negative outcomes due to monkeypox infection. There are no Imvamune®studies in this population. There is a lack of evidence of safety and efficacy of Imvamune®PEP or PrEP in this group, though at this time there is no reason to believe that vaccination would have any adverse impact on the person who is lactating or the child. There is no information on excretion of vaccine components or antigens into breastmilk; however, this is unlikely as Imvamune®is a non-replicating vaccine.

Although Imvamune® is not authorized for children, this population may be at higher risk of severe outcomes from monkeypox infection and may benefit from vaccination. Indirect evidence of clinical testing of the MVA vector as a viral vector vaccine platform for other vaccines in development, including for RSV, TB and Ebola, indicates that out of almost 2000 vaccine recipients, Imvamune® components are well tolerated in recipients under 18 years of age. There is a lack of evidence of safety and efficacy of Imvamune® PEP or PrEP in this group.

People with atopic dermatitis were a risk group with severe adverse outcomes for earlier generations of smallpox vaccines. From limited clinical testing of Imvamune®, solicited AEs were more frequent in this group including transient worsening of atopic dermatitis symptoms. Historically, previous generations of orthopoxvirus vaccines carried a risk of diffuse vaccinia virus infection for individuals with atopic dermatitis. The Imvamune® vaccine was developed to overcome those adverse effects through the use of a non-replicating virus.

4. NACI recommendation for concurrent administration:

Imvamune®given as PEP or PrEP should not be delayed due to recent receipt of an mRNA COVID-19 vaccine. If vaccine timing can be planned (i.e., prior to employment within a research laboratory), NACI recommends that Imvamune®be given at least 4 weeks after or before an mRNA vaccine for COVID-19.

First generation orthopoxvirus vaccines and mRNA COVID-19 vaccines both have a potential risk of cardiac adverse events (myocarditis). Risk for myo- or pericarditis with the newer generation non-replicating attenuated virus vaccine Imvamune® is still unknown. It would be prudent to wait for a period of at least 4 weeks before or after the administration of mRNA COVID-19 vaccine in order to prevent erroneous attribution of an AEFI to one particular vaccine or the other. This suggested minimum waiting period between vaccines is precautionary at this time. Protection from monkeypox exposure should be prioritized and recent mRNA vaccine receipt should not delay Imvamune® PEP or PrEP if protection is urgent.

Summary of Evidence and Considerations for the Vaccine:

Additional information

NACI continues to endeavour to make ethical, equitable and evidence-informed recommendations. Given the paucity of data on benefits and risks of Imvamune® in the context of a monkeypox outbreak setting, the use of Imvamune® must balance the benefits and risks of what is known and unknown about the vaccine and the disease.

It is important to obtain informed consent when offering the vaccine, and to clearly explain to potential recipients what is unknown (in addition to what is known) about the vaccine, when discussing potential risks and benefits. This is particularly important for individuals identified by NACI as special populations and for any off-label use in individuals <18 years of age.

Additionally, there is an ethical obligation to conduct close monitoring and surveillance of the use of the vaccine, in order to collect information to inform the response going forward. Both informed consent and post-market safety surveillance will be vital for the ethical implementation of an Imvamune®vaccination program, especially in pediatric populations <18 years of age when the vaccine is being used off-label.

It will be important to closely monitor who is at risk of monkeypox and provide rationale for when vaccination is needed. Additionally, to prevent stigmatization of specific populations and potentially increase vaccine acceptability, the primary focus should be identifying risk factors for transmission of monkeypox (e.g., proximity of contact, sexual activities, specific behaviours) whenever possible, rather than identifying populations perceived to be at a higher risk.

Given the limited clinical evidence on the use of Imvamune® for monkeypox PEP or PrEP, understanding of the need for, and benefit of Imvamune® in the context of a monkeypox outbreak setting is evolving.

Certain behaviours place individuals at increased risk of exposure to the monkeypox virus (e.g., proximity of contact, sexual activities, household member or behaviours that cause exposure to body fluids or fomites). Some populations are at increased risk of severe monkeypox disease due to various biological factors (e.g. individuals who are immunocompromised, pregnant, and/or, young children) and social factors that may intersect. Risk factors of severe disease and risk of exposure may overlap, further increasing risk. Any combination of these factors, as well as varying access to health care services, has the potential for disproportionate consequences for specific populations characterized by increased rates of infection, disease, and severe illness. Program planning should ensure equitable access to vaccination information and services and minimize differences in vaccine acceptance and uptake based on socioeconomic status and other socioeconomic determinants of health that may intersect.

Research Priorities

  1. Further study of the protection offered by Imvamune® vaccine against monkeypox infection and disease (in PrEP and PEP scenarios), including:
    1. Understanding which immune responses are protective against infection and disease and defining protective thresholds
    2. Understanding how the impact of previous orthopox infection or vaccination impacts the protection offered by Imvamune®
    3. Real-world evidence on the vaccine effectiveness of Imvamune®against monkeypox and for the use of single dose PrEP and PEP.
  2. Further studies to further inform on the safety of Imvamune® vaccine including both clinical trials and post-market safety surveillance.
  3. Safety in special populations, including people who are pregnant or breastfeeding, children <18 years of age, and people who are immunocompromised should also be assessed by targeted clinical trials.
  4. Further study into the epidemiology of the disease to better understand the modes of transmission, the disease presentation, and to identify the populations at highest risk for severe disease in order to inform and optimize disease prevention strategies.
Table 2. Strength of NACI Recommendations
Strength of NACI Recommendation
based on factors not isolated to strength of evidence
(e.g., public health need)
STRONG DISCRETIONARY
Wording "should/should not be offered" "may/may not be offered"
Rationale Known/anticipated advantages outweigh known/anticipated disadvantages ("should"),
OR Known/Anticipated disadvantages outweigh known/anticipated advantages ("should not")
Known/anticipated advantages are closely balanced with known/anticipated disadvantages, OR uncertainty in the evidence of advantages and disadvantages exists
Implication A strong recommendation applies to most populations/individuals and should be followed unless a clear and compelling rationale for an alternative approach is present. A discretionary recommendation may be considered for some populations/individuals in some circumstances. Alternative approaches may be reasonable.

Abbreviations

AD
Atopic dermatitis
AEs
Adverse events
AEFI
Adverse events following immunization
AIDS
Acquired immunodeficiency syndrome
BC
British Columbia
CIC
Canadian Immunization Committee
DART
Developmental and Reproductive Toxicology
EUNDS
Extraordinary Use New Drug Submission
EV
Eczema vaccinatum
HCID WG
High Consequence Infectious Disease working group
HIV
Human immunodeficiency virus
HSCT
Haematopoietic stem cell transplantation
GPHIN
Global Public Health Intelligence
LGBTQ2S+
Lesbian, Gay, Bisexual, Transgender, Queer or Questioning, and Two-Spirit
MVA-BN
Modified Vaccinia Ankara-Bavarian Nordic
NACI
National Advisory Committee on Immunization
PHAC
Public Health Agency of Canada
PCR
Polymerase chain reaction
PEP
Post-Exposure Prophylaxis
PHECG
Public Health Ethics Consultative Groups
PrEP
Pre-Exposure Prophylaxis
RSV
Respiratory Syncytial Virus
TB
Tuberculosis
US
United States
UK
United Kingdom
VE
Vaccine effectiveness
VSWG
Vaccine Safety Working Group
WHO
World Health Organization

Acknowledgements

This statement was prepared by: A Killikelly, N Brousseau, M Plamondon, R Krishnan, MY Yeung, N Forbes, R Harrison, S Deeks, and MC Tunis, on behalf of NACI.

NACI gratefully acknowledges the contribution of: J Cao, A Coady, J Courtemanche, S Elliot, P Gorton, M Haavaldsrud, C Irwin, C Jensen, C Mauviel, L Murphy, M Patel, R Pless, G Pulle, K Rutledge-Taylor, M Salvadori, E Schillberg, R Singaravelu, J Strong, E Tice, K Wilkinson, E Wong, R Ximenes, J Zafack, L Zhao, and MC Lamontagne.

NACI members: S Deeks (Chair), R Harrison (Vice-Chair), M Andrew, J Bettinger, N Brousseau, H Decaluwe, P De Wals, E Dubé, V Dubey, K Hildebrand, K Klein, M O'Driscoll, J Papenburg, A Pham-Huy, B Sander, and S Wilson.

Liaison representatives: L Bill (Canadian Indigenous Nurses Association), LM Bucci (Canadian Public Health Association), E Castillo (Society of Obstetricians and Gynaecologists of Canada), J Comeau (Association of Medical Microbiology and Infectious Disease Control), L Dupuis (Canadian Nurses Association), E Adams (Indigenous Physicians Association of Canada), J Hui (College of Family Physicians of Canada), M Lavoie (Council of Chief Medical Officers of Health), D Moore (Canadian Paediatric Society), M Naus (Canadian Immunization Committee), and A Ung (Canadian Pharmacists Association).

Ex-officio representatives: V Beswick-Escanlar (National Defence and the Canadian Armed Forces, E Henry (Centre for Immunization and Respiratory Infectious Diseases (CIRID), PHAC), M Lacroix (Public Health Ethics Consultative Group, PHAC), C Lourenco (Biologic and Radiopharmaceutical Drugs Directorate, Health Canada), S Ogunnaike-Cooke (CIRID, PHAC), K Robinson (Marketed Health Products Directorate, HC), G Poliquin (National Microbiology Laboratory, PHAC), and T Wong (First Nations and Inuit Health Branch, Indigenous Services Canada).

NACI High Consequence Infectious Disease Working Group

Members: N Brousseau (Chair), CA Buchan, YG Bui, E Castillo, R Harrison, K Hildebrand, M Libman, M Murti, V Poliquin, A Rao, C Quach, and S Wilson.

PHAC/HC participants: A Coady, J Cao, R Farley, P Gorton, C Irwin, C Jensen, A Killikelly, R Krishnan, T Lee, M Patel, M Plamondon, R Pless, G Pulle, K Rutledge-Taylor, R Singaravelu, J Strong, MC Tunis, K Wilkinson, E Wong, R Ximenes, MY Yeung, and L Zhao.

Appendix A: Clinical and Preclinical Data on Imvamune®

Data for Pre-Exposure Prophylaxis (PrEP)

Safety Data for Imvamune®

The safety of Imvamune was assessed in the limited context of clinical trials and Imvamune® has not been administered at the scale needed to predict low frequency adverse effects. In the limited safety assessments that have been done, no signals of concern for Imvamune®have been identified.

Clinical Immunogenicity and Indirect Evidence of Protection by Imvamune®

There are no data indicating the efficacy or effectiveness of Imvamune®vaccination against monkeypox infection or disease in the context of PrEP or PEP. Clinical data for Imvamune®PrEP are limited to clinical immunogenicity or indirect protection from vaccinia (the virus used for 1st or 2nd generation smallpox vaccines). There is no established threshold above which immune responses to any orthopoxviruses are considered protective therefore the interpretation of the decline or boosting of immune responses remains unclear. Clinical protection from symptoms of vaccinia infection may not be indicative of protection against monkeypox.

Preclinical Immunogenicity and Efficacy Data for Imvamune®

Given the limited clinical data available to demonstrate Imvamune® efficacy and effectiveness against monkeypox infection and disease, insight may be gained from preclinical data for MVA-BN (the non-replicating virus in Imvamune® vaccines). Immune responses and protection from disease outcomes have been demonstrated across different animal models however it remains unclear the degree to which preclinical results will predict outcomes in humans.

Data for Post-Exposure Prophylaxis (PEP)

Safety Data for Imvamune®

There are no safety data available to demonstrate the safety of Imvamune® in the context of PEP. However, the safety of Imvamune® in a PEP context can be inferred from studies in a PrEP context. It is unclear how previous orthopoxvirus exposure could affect Imvamune®safety.

Clinical Immunogenicity and Indirect Evidence of Protection by Imvamune®

There are no data indicating the efficacy or effectiveness of Imvamune® vaccination against monkeypox infection or disease in the context of PrEP or PEP. Clinical data for Imvamune® PEP can be inferred from clinical pre-exposure testing where immunological responses were detected within 2 weeks of vaccination Footnote 11. Timing of PEP could be inferred from studies of early generation smallpox vaccines, however it is unknown how these smallpox studies directly relate to protection from monkeypox by Imvamune®.

Preclinical Immunogenicity and Efficacy Data for Imvamune®

Given the limited clinical data available to demonstrate Imvamune® efficacy and effectiveness against monkeypox infection and disease, insight may be gained from preclinical data for MVA-BN (the non-replicating virus in Imvamune® vaccines). Immune responses and protection from disease outcomes have been demonstrated across different animal models; however, it remains unclear the degree to which preclinical results will predict outcomes in humans.

Imvamune® in Special Populations

Data are even more limited for populations either at risk for more severe outcomes due to monkeypox infection, or who may be at higher risk for adverse events due to vaccination. Small clinical trials of Imvamune® in people infected with HIV and in people with atopic dermatitis offer limited safety and immunogenicity data. Imvamune® has never been tested in children (<18y), people who are pregnant or people who are lactating, though limited data may be available from testing the MVA vaccine platform for other viruses. Limited indirect data for these groups have been used to make recommendations.

Immunocompromised individuals:

Pregnant and lactating people:

Children (< 18 years old):

Individuals with atopic dermatitis:

References

Footnote 1

Monkeypox [Internet]. Geneva (CH): World Health Organization; 2022 May 19 [cited 2022 Jun 2]. Available from: https://www.who.int/news-room/fact-sheets/detail/monkeypox.

Return to footnote 1 referrer

Footnote 2

Adler H, Gould S, Hine P, Snell LB, Wong W, Houlihan CF, et al. Clinical features and management of human monkeypox: a retrospective observational study in the UK. Lancet Infect Dis. 2022 May 24. doi 10.1016/S1473-3099(22)00228-6.

Return to footnote 2 referrer

Footnote 3

Petersen E, Kantele A, Koopmans M, Asogun D, Yinka-Ogunleye A, Ihekweazu C, et al. Human Monkeypox: Epidemiologic and Clinical Characteristics, Diagnosis, and Prevention. Infect Dis Clin North Am. 2019 Dec;33(4):1027,1043. doi: 10.1016/j.idc.2019.03.001.

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Footnote 4

Mbala PK, Huggins JW, Riu-Rovira T, Ahuka SM, Mulembakani P, Rimoin AW, et al. Maternal and Fetal Outcomes Among Pregnant Women With Human Monkeypox Infection in the Democratic Republic of Congo. J Infect Dis. 2017 Oct 1;216(7):824,828. doi: 10.1093/infdis/jix260.

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Footnote 5

FINE PEM, JEZEK Z, GRAB B, DIXON H. The Transmission Potential of Monkeypox Virus in Human Populations. Int J Epidemiol. 1988 Sep 01;17(3):643,650. https://doi.org/10.1093/ije/17.3.643.

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Footnote 6

PRODUCT MONOGRAPH INCLUDING PATIENT MEDICATION INFORMATION: IMVAMUNE® Smallpox and Monkeypox Vaccine [Internet]. Copenhagen (DK): Bavarian Nordic [updated 2021 Nov 26; cited 2022 Jun 2]. Available from: https://pdf.hres.ca/dpd_pm/00063755.PDF.

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Footnote 7

Verheust C, Goossens M, Pauwels K, Breyer D. Biosafety aspects of modified vaccinia virus Ankara (MVA)-based vectors used for gene therapy or vaccination. Vaccine. 2012 Mar 30;30(16):2623,2632. doi:10.1016/j.vaccine.2012.02.016.

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Footnote 8

Volkmann A, Williamson AL, Weidenthaler H, Meyer TPH, Robertson JS, Excler JL, et al. The Brighton Collaboration standardized template for collection of key information for risk/benefit assessment of a Modified Vaccinia Ankara (MVA) vaccine platform. Vaccine. 2021 May 21;39(22):3067,3080. doi: 10.1016/j.vaccine.2020.08.050.

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Footnote 9

Russo AT, Berhanu A, Bigger CB, Prigge J, Silvera PM, Grosenbach DW, et al. Co-administration of tecovirimat and ACAM2000™ in non-human primates: Effect of tecovirimat treatment on ACAM2000 immunogenicity and efficacy versus lethal monkeypox virus challenge. Vaccine. 2020 Jan 16;38(3):644,654. doi: 10.1016/j.vaccine.2019.10.049.

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Footnote 10

PRODUCT MONOGRAPH INCLUDING PATIENT MEDICATION INFORMATION: IMVAMUNE Smallpox and Monkeypox Vaccine [Internet]. Copenhagen (DK): Bavarian Nordic [updated 2020 Nov 5; cited 2022 Jun 2]. Available from: https://pdf.hres.ca/dpd_pm/00058622.PDF.

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Footnote 11

Pittman PR, Hahn M, Lee HS, Koca C, Samy N, Schmidt D, et al. Phase 3 Efficacy Trial of Modified Vaccinia Ankara as a Vaccine against Smallpox. N Engl J Med. 2019 Nov 14;381(20):1897,1908. doi: 10.1056/NEJMoa1817307.

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Footnote 12

An Open-Label Phase II Study to Evaluate Immunogenicity and Safety of a Single IMVAMUNE Booster Vaccination Two Years After the Last IMVAMUNE Vaccination in Former POX-MVA-005 Vaccinees [Internet]. Bethesda (MD): ClinicalTrials.gov [updated 2019 Mar 13; cited 2022 Jun 2]. Available from: https://clinicaltrials.gov/ct2/show/NCT00686582?term=POX-MVA-023&draw=2&rank=1.

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Footnote 13

An Open-Label Phase II Study to Evaluate Immunogenicity and Safety of a Single IMVAMUNE Booster Vaccination Two Years After the Last IMVAMUNE Vaccination in Former POX-MVA-005 Vaccinees [Internet]. Bethesda (MD): ClinicalTrials.gov [updated 2019 Mar 13; cited 2022 Jun 2]. Available from: https://clinicaltrials.gov/ct2/show/NCT00686582?term=pox-mva-005&draw=2&rank=1.

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Footnote 14

Vollmar J, Arndtz N, Eckl KM, Thomsen T, Petzold B, Mateo L, et al. Safety and immunogenicity of IMVAMUNE, a promising candidate as a third generation smallpox vaccine. Vaccine. 2006 Mar 15;24(12):2065,2070. doi: 10.1016/j.vaccine.2005.11.022.

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Footnote 15

A Randomized, Double-blind, Placebo-controlled Study on Immunogenicity and Safety of MVA-BN (IMVAMUNE™) Smallpox Vaccine in Healthy Subjects [Internet]. Bethesda (MD): ClinicalTrials.gov [updated 2019 Mar 6; cited 2022 Jun 6]. Available from: https://clinicaltrials.gov/ct2/show/results/NCT00316524?term=pox-mva-005&draw=2&rank=2.

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Footnote 16

Greenberg RN, Hay CM, Stapleton JT, Marbury TC, Wagner E, Kreitmeir E, et al. A Randomized, Double-Blind, Placebo-Controlled Phase II Trial Investigating the Safety and Immunogenicity of Modified Vaccinia Ankara Smallpox Vaccine (MVA-BN®) in 56-80-Year-Old Subjects. Plos one. 2016 Jun 21;11(6):e0157335. doi: 10.1371/journal.pone.0157335.

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Footnote 17

Meseda CA, Garcia AD, Kumar A, Mayer AE, Manischewitz J, King LR, et al. Enhanced immunogenicity and protective effect conferred by vaccination with combinations of modified vaccinia virus Ankara and licensed smallpox vaccine Dryvax in a mouse model. Virology. 2005 Sep 1;339(2):164,175. doi: 10.1016/j.virol.2005.06.002.

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Footnote 18

Phelps AL, Gates AJ, Hillier M, Eastaugh L, Ulaeto DO. Comparative efficacy of modified vaccinia Ankara (MVA) as a potential replacement smallpox vaccine. Vaccine. 2007 Jan 2;25(1):34,42. doi: 10.1016/j.vaccine.2006.07.022.

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Footnote 19

Volz A, Langenmayer M, Jany S, Kalinke U, Sutter G. Rapid expansion of CD8+ T cells in wild-type and type I interferon receptor-deficient mice correlates with protection after low-dose emergency immunization with modified vaccinia virus Ankara. J Virol. 2014 Aug 19;88(18):10946,10957. doi: 10.1128/JVI.00945-14.

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Footnote 20

Wyatt LS, Earl PL, Eller LA, Moss B. Highly attenuated smallpox vaccine protects mice with and without immune deficiencies against pathogenic vaccinia virus challenge. Proc Natl Acad Sci U S A. 2004 Mar 30;101(13):4590,4595. doi: 10.1073/pnas.0401165101.

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Footnote 21

Earl PL, Americo JL, Wyatt LS, Eller LA, Whitbeck JC, Cohen GH, et al. Immunogenicity of a highly attenuated MVA smallpox vaccine and protection against monkeypox. Nature. 2004 Mar 11;428(6979):182,185. doi: 10.1038/nature02331.

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Footnote 22

Hatch GJ, Graham VA, Bewley KR, Tree JA, Dennis M, Taylor I, et al. Assessment of the protective effect of Imvamune and Acam2000 vaccines against aerosolized monkeypox virus in cynomolgus macaques. J Virol. 2013 Jun 27;87(14):7805,7815. doi: 10.1128/JVI.03481-12.

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Footnote 23

Stittelaar KJ, van Amerongen G, Kondova I, Kuiken T, van Lavieren RF, Pistoor FH, et al. Modified vaccinia virus Ankara protects macaques against respiratory challenge with monkeypox virus. J Virol. 2005 Jun;79(12):7845,7851. doi: 10.1128/JVI.79.12.7845-7851.2005.

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Footnote 24

Keckler MS, Carroll DS, Gallardo-Romero NF, Lash RR, Salzer JS, Weiss SL, et al. Establishment of the black-tailed prairie dog (Cynomys ludovicianus) as a novel animal model for comparing smallpox vaccines administered preexposure in both high- and low-dose monkeypox virus challenges. J Virol. 2011 Aug;85(15):7683,7698. doi: 10.1128/JVI.02174-10.

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Footnote 25

Massoudi MS, Barker L, Schwartz B. Effectiveness of postexposure vaccination for the prevention of smallpox: results of a delphi analysis. J Infect Dis. 2003 Sep 16;188(7):973,976. doi: 10.1086/378357.

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Footnote 26

Paran N, Suezer Y, Lustig S, Israely T, Schwantes A, Melamed S, et al. Postexposure immunization with modified vaccinia virus Ankara or conventional Lister vaccine provides solid protection in a murine model of human smallpox. J Infect Dis. 2009 Jan 1;199(1):39,48. doi: 10.1086/595565.

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Footnote 27

Samuelsson C, Hausmann J, Lauterbach H, Schmidt M, Akira S, Wagner H, et al. Survival of lethal poxvirus infection in mice depends on TLR9, and therapeutic vaccination provides protection. J Clin Invest. 2008 Apr 8;118(5):1776,1784. doi: 10.1172/JCI33940.

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Footnote 28

Keckler MS, Salzer JS, Patel N, Townsend MB, Nakazawa YJ, Doty JB, et al. IMVAMUNE(®) and ACAM2000(®) Provide Different Protection against Disease When Administered Postexposure in an Intranasal Monkeypox Challenge Prairie Dog Model. Vaccines (Basel). 2020 Jul 20;8(3):396. doi: 10.3390/vaccines8030396.

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Footnote 29

Overton ET, Stapleton J, Frank I, Hassler S, Goepfert PA, Barker D, et al. Safety and Immunogenicity of Modified Vaccinia Ankara-Bavarian Nordic Smallpox Vaccine in Vaccinia-Naive and Experienced Human Immunodeficiency Virus-Infected Individuals: An Open-Label, Controlled Clinical Phase II Trial. Open Forum Infect Dis. 2015 May 5;2(2):ofv040. doi: 10.1093/ofid/ofv040.

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Footnote 30

Greenberg RN, Overton ET, Haas DW, Frank I, Goldman M, von Krempelhuber A, et al. Safety, immunogenicity, and surrogate markers of clinical efficacy for modified vaccinia Ankara as a smallpox vaccine in HIV-infected subjects. J Infect Dis. 2013 Mar 1;207(5):749,758. doi: 10.1093/infdis/jis753.

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Footnote 31

Overton ET, Lawrence SJ, Stapleton JT, Weidenthaler H, Schmidt D, Koenen B, et al. A randomized phase II trial to compare safety and immunogenicity of the MVA-BN smallpox vaccine at various doses in adults with a history of AIDS. Vaccine. 2020 Mar 4;38(11):2600,2607. doi: 10.1016/j.vaccine.2020.01.058.

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Footnote 32

Walsh SR, Wilck MB, Dominguez DJ, Zablowsky E, Bajimaya S, Gagne LS, et al. Safety and immunogenicity of modified vaccinia Ankara in hematopoietic stem cell transplant recipients: a randomized, controlled trial. J Infect Dis. 2013 Jun 15;207(12):1888,1897. doi: 10.1093/infdis/jit105.

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Footnote 33

Recommendations for the use of pre and post exposure vaccination during a monkeypox incident [Internet]. London (UK): UK Health Security Agency [updated 2022 Jun 1; cited 2022 Jun 2]. Available from: https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/1080615/Recommendations-for-pre-and-post-exposure-vaccination-during-a-monkeypox-incident-1-june-2022.pdf.

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Footnote 34

JYNNEOS (Smallpox and Monkeypox Vaccine, Live, Non- replicating) suspension for subcutaneous injection Initial U.S. Approval: 2019 [Internet]. Silver Spring (MD): U.S. Food and Drug Administration [updated 2021 Jun; cited 2022 Jun 2]. Available from: https://www.fda.gov/media/131078/download.

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Footnote 35

A Study of a 2-dose Ebola Vaccine Regimen of Ad26.ZEBOV Followed by MVA-BN-Filo in Healthy Pregnant Women (INGABO) [Internet]. Bethesda (MD): ClinicalTrials.gov [updated 2022 May 11; cited 2022 jun 2]. Available from: https://clinicaltrials.gov/ct2/show/NCT04556526?term=MVA+vaccine&age=1&phase=2&draw=2&rank=2

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Footnote 36

Afolabi MO, Ishola D, Manno D, Keshinro B, Bockstal V, Rogers B, et al. Safety and immunogenicity of the two-dose heterologous Ad26.ZEBOV and MVA-BN-Filo Ebola vaccine regimen in children in Sierra Leone: a randomised, double-blind, controlled trial. Lancet Infect Dis. 2022 Jan;22(1):110,122. doi: 10.1016/S1473-3099(21)00128-6.

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Footnote 37

Study to Evaluate Safety, Dose Response and Immunogenicity of the Measles Vaccine MVA mBN85B in Healthy Children Aged 6 Months to 6 Years [Internet]. Bethesda (MD): ClinicalTrials.gov [updated 2012 Jul 27; cited 2022 Jun 2]. Available from: https://clinicaltrials.gov/ct2/show/NCT00891007?term=NCT00891007&draw=2&rank=1.

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Footnote 38

Lienert F. Personal communication. Request for Information about Ivamune PrEP/PEP. Bavarian Nordic. 2022 May 24.

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Footnote 39

von Sonnenburg F, Perona P, Darsow U, Ring J, von Krempelhuber A, Vollmar J, et al. Safety and immunogenicity of modified vaccinia Ankara as a smallpox vaccine in people with atopic dermatitis. Vaccine. 2014 Sep 29;32(43):5696,5702. doi: 10.1016/j.vaccine.2014.08.022.

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Footnote 40

Greenberg RN, Hurley MY, Dinh DV, Mraz S, Vera JG, von Bredow D, et al. A Multicenter, Open-Label, Controlled Phase II Study to Evaluate Safety and Immunogenicity of MVA Smallpox Vaccine (IMVAMUNE) in 18-40 Year Old Subjects with Diagnosed Atopic Dermatitis. PLoS One. 2015 Oct 6;10(10):e0138348. doi: 10.1371/journal.pone.0138348.

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