GACVS had previously considered the safety of smallpox vaccination.¹⁶ The Committee was provided with updated safety information for 1st, 2nd and 3rd generation smallpox vaccines in order to make informed decisions regarding emergency smallpox vaccine stockpiling and future use. The safety update also included an overview of the safety of smallpox vaccines used in the smallpox eradication efforts. Detailed safety information was provided for the currently licensed replicating 2nd generation ACAM2000 and the non-replicating 3rd generation Imvanex/Imvamune smallpox vaccines.

ACAM2000®, manufactured by Sanofi Pasteur Biologics, LLC is a live vaccinia virus smallpox vaccine derived by plaque purification from previously licensed calf lymph produced vaccine (Dryvax) and manufactured in Vero cells. It is indicated for active immunization against smallpox disease for persons determined to be at high risk for smallpox infection. ACAM2000 vaccine is currently licensed in the USA, Australia, and Singapore. Serious adverse effects reported from clinical trials with ACAM2000 include myopericarditis and cardiomyopathy. Three safety surveillance studies are ongoing, including a myopericarditis registry to document the natural history of myopericarditis following ACAM2000 vaccination, a prospective cohort study in deployed military personnel, and an enhanced safety surveillance study in military personnel to evaluate the rates of suspected and confirmed myopericarditis in temporal association with ACAM2000 vaccination. Apart from the known signal of myopericarditis observed in these studies, rare serious sequelae, e.g. disseminated vaccinia, eczema vaccinatum and encephalopathy, have not been observed. The updated safety information for ACAM2000 did not reveal any new areas of concern after administration to approximately 1 million people.

Imvanex/Imvamune®, manufactured by Bavarian Nordic is a modified vaccinia virus Ankara derived from replication-competent dermal vaccinia strain Ankara attenuated after >570 continuous passages in primary chicken embryo fibroblasts that has undergone 6 rounds of plaque purification and is propagated in serum-free conditions. Due to its high level of attenuation, it is no longer replication-competent in human cell lines. It is indicated for active immunization against smallpox in adults and approved in Europe and Canada. Safety summary data from completed and ongoing clinical trials in which >7600 individuals received the vaccine, including vaccinia naive and experienced populations, HIV positive subjects and persons with atopic dermatitis, showed that the vast majority of events represented local and systemic reactions reported as mild to moderate and resolved rapidly without intervention. The vaccine was well tolerated with no clinically relevant differences between the populations studied. There was one unconfirmed case of “possible acute pericarditis” in the recently completed phase 3 clinical study that was considered possibly vaccine related by the investigator. However, no confirmed case of myopericarditis or any other cardiac inflammatory event in any Imvanex/Imvamune clinical trial was observed.

GACVS noted that overall, no new safety concerns have been observed with the ACAM2000 and Imvanex/Imvamune smallpox vaccines. There is little safety information on these newer smallpox vaccines among pregnant women and it is not known whether the safety profiles of these vaccines differ depending on ethnic background. There are also no data in pediatric subjects and GACVS noted that in the absence of circulating smallpox, these vaccines should not be used in pediatric populations. The vaccines have been shown to be immunogenic and protective against lethal orthopoxvirus challenge in animal models.

GACVS recommended that any use of smallpox vaccines be guided by the anticipated risk versus benefit presented during various outbreak or exposure scenarios. For example, in a situation of a widespread smallpox outbreak, the risks of adverse events following vaccination may be acceptable. While the risk of a widespread smallpox outbreak is low, outbreaks or exposures to other orthopoxviruses that are more limited in size and scope may occur. Under these scenarios, adequate screening procedures may minimize the risks associated with vaccination.

¹⁶ See No. 3, 2004, p. 20.

Full report of GACVS meeting of 2-3 December 2015, published in the WHO Weekly Epidemiological Record of 22 January 2016

GACVS has previously considered the safety of smallpox vaccination.⁴ The Committee was provided with an up-dated account of the safety of smallpox vaccination, based on 38 759 persons vaccinated in the United States since January 2003, covering 65% of health care workers and at least one health care worker in 45% of hospitals. There is, in addition, a pregnancy registry of 160 women exposed to smallpox vaccine during or immediately before pregnancy, identifiable by testing. Consistent adverse effects reported in smallpox vaccinees have been myopericarditis and dilated cardiomyopathy; the frequency of each adverse effect exceeds what might have occurred by coincidence.

⁴ See No. 32, 2003, pp 282–284

Full report of GACVS meeting of 3-4 December 2003, published in the WHO Weekly Epidemiological Record on 16 January 2004

Statement on January 2004

An updated account of the safety of smallpox vaccination, was presented to the Global Advisory Committee on Vaccine Safety (GACVS) at its ninth meeting in Geneva, Switzerland on December 3-4, 2003. Two expert reports on the safety of smallpox vaccination were previously presented to GACVS, including detailed reviews of historical data and of recent experience, particularly in the United States.1 The data highlighted the large variation in the pathogenicity of previously used strains and it was noted that safety data gained with the older vaccines may not necessarily apply to newly developed smallpox vaccines and it should not be assumed that they will be safer.

The Committee concluded the data were insufficient to define the incidence of adverse events in primary vaccinees as opposed to individuals re-vaccinated after a long interval. The Committee noted the importance of adverse event surveillance programs being open-minded so that hitherto unrecognized events might be detected. The Committee further noted that if the vaccine is being used in mass campaigns, it would be especially important for smallpox immunization programmes to be supported by adverse event monitoring. Implementation in settings where there is no educational programme and careful exclusion of volunteers at potentially increased relative risks (e.g., those with HIV) could possibly result in enhanced vaccine risks. The risk of exposure should be carefully considered in relation to each specific scenario that may arise. In mass vaccination, the impact of vaccine reactions may constitute a significant health burden.

The current update was based on 38,759 persons vaccinated in the United States since January 2003, covering 65% of health care workers and at least one health care worker in 45% of hospitals. There is, in addition, a pregnancy registry of 160 women exposed to smallpox vaccine during or immediately before pregnancy, identifiable by testing; data from the pregnancy registry are pending. The Committee noted that consistent adverse effects reported in smallpox vaccinees have been myopericarditis and dilated cardiomyopathy (both not previously well recognized as serious adverse events to the smallpox vaccine); the frequency of each adverse effect exceeds what might have occurred by coincidence.

The Committee did not change the conclusions from its June 2003 meeting1 that there is a real risk of serious adverse events following immunization with smallpox vaccine, including safety issues that have not previously been recognized, that there may be significant potential risks to contacts of vaccinees, and that implementation of immunization would require significant capacity and resources. The Committee will continue to monitor the safety of smallpox vaccines.

¹WER No. 32, 2003, pp. 282–284.

Statement on July 2003

Two expert reports on the safety of smallpox vaccines were presented to the Global Advisory Committee on Vaccine Safety (GACVS) at its eighth meeting in Geneva, Switzerland on June 11-12, 2003. The reports included a detailed review of the safety of smallpox vaccine based on historical data as well as recent experience, particularly in the United States. The data highlighted the large variation in the pathogenicity of previously used strains and it was noted that safety data gained with the older vaccines may not necessarily apply to newly developed smallpox vaccines and it should not be assumed that they will be safer.

Special attention was paid to the paucity of data regarding safety of immunization in subjects less than 18 years of age, age-related risks with the vaccine in general, and outcomes in women immunized during pregnancy. Current data are insufficient to define the incidence of adverse events in primary vaccinees as opposed to individuals re-vaccinated after a long interval. The Committee noted the importance of adverse event surveillance programs being open-minded so that hitherto unrecognized events might be detected. If the vaccine is being used in mass campaigns, it would be especially important for smallpox immunization programmes to be supported by adverse event monitoring. Implementation in settings where there is no educational programme and careful exclusion of volunteers at potentially increased relative risks (e.g., those with HIV) could possibly result in enhanced vaccine risks. The risk of exposure should be carefully considered in relation to each specific scenario that may arise. In mass vaccination, the impact of vaccine reactions may constitute a significant health burden.

The Committee concluded that there is a real risk of serious adverse events following immunization with smallpox vaccine, including safety issues that have not previously been recognized, that there may be potential risks to contacts of vaccinees, and that implementation of immunization would require capacity and resources. The committee will continue to monitor the safety of smallpox vaccines.

The GACVS is a scientific advisory body established by WHO to provide a reliable and independent scientific assessment of vaccine safety issues in order to respond promptly, efficiently and with scientific rigour to such issues. Membership includes experts from around the world in the fields of epidemiology, paediatrics, internal medicine, pharmacology and toxicology, infectious diseases, public health, immunology and autoimmunity, drug regulation, and safety.