Table 1. Knowns and unknowns^a.

Knowns		Unknowns
Pre-exposure prophylaxis
From early-stage clinical trials, most of the reported AEFIs were mild to moderate and resolved within seven days following vaccination. Some cardiac AEFIs were reported in Imvamune® recipients and none were considered serious. Indirect clinical immunological evidence showed that Imvamune was able to generate immune responses by week two after a first dose, and comparable immune responses to previous generation smallpox vaccines after two doses by week six. Indirect clinical evidence showed that two doses of Imvamune was able to generate protection from symptomatic vaccinia (Orthopoxvirus related to monkeypox). Imvamune immune responses may decrease after two years. Immune responses to booster doses of Imvamune were fast and to the level of primary series responses.		The efficacy or effectiveness of Imvamune PrEP against monkeypox infection or disease is unknown. There were no direct efficacy or effectiveness data for Imvamune against monkeypox. There was limited safety data for Imvamune PrEP. The degree to which preclinical, immunological or Othopoxvirus data was predictive of Imvamune protection or durability against monkeypox is unknown. The number of doses, or dose interval, for optimal protection by Imvamune PrEP in immunocompetent adults without underlying medical conditions is unknown. The protection offered by previous smallpox vaccination (potentially from decades ago) and the best use of Imvamune PrEP in those previously vaccinated is unknown. Due to the limited context of Imvamune use (i.e. clinical trials), low frequency AEFIs (frequency fewer than one in 10,000) are unknown. The degree to which previous infection or vaccination impacts the efficacy/effectiveness and safety Imvamune PrEP is uknown.
Post-exposure prophylaxis
Indirect preclinical immunological evidence showed that Imvamune PEP was able to generate comparable immune responses to previous generation smallpox vaccines. Based on historical data for first generation vaccination against variola, the earlier the PEP was given, the better the protection from disease. Indirect clinical immunological evidence from PrEP studies showed that Imvamune was able to generate immune responses by week two after a first dose, and comparable immune responses to previous generation smallpox vaccines after two doses by week six.		The safety, efficacy or effectiveness of Imvamune PEP against monkeypox infection or disease is unknown. There were no direct safety, efficacy or effectiveness data for Imvamune PEP against monkeypox. The number of doses, dose interval or timing from exposure, for optimal protection by Imvamune PEP in immunocompetent adults without underlying medical conditions is unknown. The degree to which previous infection or vaccination impacts the efficacy/effectiveness and safety Imvamune PEP is unknown.
Special populations
Immunosuppressed individuals	Based on limited clinical study, safety among people living with HIV (CD4 at least 100 cells/µL) and HSCT seemed comparable with non-immunosuppressed controls. Compared to people without HIV, individuals living with HIV may have had lower immune responses to one dose of Imvamune and may have had decreased durability of immune responses. Imvamune was well tolerated in 20 individuals who received hematopoietic stem cell transplant.	The efficacy or effectiveness of Imvamune PEP or PrEP against monkeypox infection or disease is unknown. There were no direct efficacy or effectiveness data for Imvamune in this population against monkeypox. There were limited safety data for Imvamune PrEP. It is not yet clear if some immunocompromised groups will be less protected by the vaccine and may require specific vaccine doses, intervals or antigen levels.
Pregnant and breastfeeding individuals	No safety concerns were identified during limited clinical and preclinical testing of Imvamune.	The safety, efficacy or effectiveness of Imvamune PEP or PrEP against monkeypox infection or disease is unknown. Imvamune has never been tested in this population. There were no direct safety, efficacy or effectiveness data for Imvamune in this population against monkeypox.
Children younger than 18 years	No safety concerns were identified in limited clinical testing of Imvamune-like vaccines in approximately 2,000 children under 18 years of age.	The safety, efficacy or effectiveness of Imvamune PEP or PrEP against monkeypox infection or disease is unknown. Imvamune has never been tested in this population. There are no direct safety, efficacy or effectiveness data for Imvamune in this population against monkeypox. It is not yet clear if some age groups may require specific vaccine doses, intervals or antigen levels or if there is a minimum age for vaccination.
Individuals with AD	In limited clinical testing, Imvamune was well tolerated in individuals with AD, though individuals with AD may experience a higher frequency of local and systemic reactogenicity compared to those without AD.	The safety, efficacy or effectiveness of Imvamune PEP or PrEP against monkeypox infection or disease is unknown. There are no direct efficacy or effectiveness data for Imvamune in this population against monkeypox. There are limited safety data for Imvamune.

Abbreviations: AEFIs, adverse events following immunization; AD, atopic dermatitis; HSCT, hematopoietic stem cell transplantation; PEP, post-exposure prophylaxis; PrEP, pre-exposure prophylaxis

^a Summarized from the Interim guidance on the use of Imvamune in the context of monkeypox outbreaks in Canada ((5))