In 2004, the US Department of Homeland Security (DHS) declared that Variola major, the virus that causes smallpox, presents a material threat to national security, and issued a Material Threat Determination (MTD). A DHS MTD is a prerequisite for medical countermeasure procurement under Project BioShield (42 USC §247d-6b[c][2]). This finding was a result of 6 security concerns: (1) intelligence gathered during the 1990s suggesting that Variola was manufactured and stored in the former Soviet Union; (2) the aerosol infectivity of the virus; (3) the relative ease of large-scale production; (4) an increasing susceptibility of the US population to orthopoxviruses due to the suspension of routine smallpox vaccination; (5) the aging vaccine supply; and (6) the baseline threat of terrorism, recently manifested in the September 11th and subsequent anthrax attacks of 2001. The MTD has been in effect for a decade, and its continued relevance was underscored by the 2014 discovery of forgotten and unaccounted for vials of viable smallpox at a Food and Drug Administration (FDA) laboratory in a suburb of Washington, DC.
Fears have also emerged regarding the spread of Variola’s viral cousins—monkeypox and cowpox—against which smallpox vaccine provides protection. In the 1970s, secondary protection against these diseases was well known but deemed less important given the extent of smallpox infections. Recent evidence suggests, however, that these pathogens pose a growing threat to an increasingly naïve population, as cases of monkeypox and cowpox have increased steadily in recent years. In June 2003, a total of 81 primary human cases of monkeypox infection were reported in the United States after patients had contact with infected pet prairie dogs. All patients reported direct contact with an infected prairie dog, although human-to-human transmission could not be ruled out.Reference Reed, Melski and Graham 1 Monkeypox and cowpox pathogens have also infected a range of new animal hosts, offering additional venues for spread of disease. In addition, military personnel may be at greater risk of monkeypox exposure when deployed in sub-Saharan Africa, where the disease is endemic.
Both pathogens are also difficult (if not impossible) to eradicate, as they exist naturally in rodents and other creatures. Of gravest concern is that monkeypox could mutate, becoming much more transmissible and/or lethal to humans.Reference Shah 2 In addition, experts have concluded that biological threats, such as Variola or other orthopox viruses, can be created synthetically in a laboratory. 3 Scientists have already synthesized several organisms of comparable or even larger size.Reference Gibson, Benders and Andrews-Pfannkoch 4
In response to these concerns, the Department of Defense (DoD) reinstituted a military vaccination program using the available, licensed, and replicating smallpox vaccine (Dryvax vaccine, Pfizer, Inc), and, later, a newer generation smallpox vaccine (ACAM2000, Sanofi Pasteur), primarily for troops deployed to Southwest Asia and the Republic of Korea in 2002.Reference Darling and Woods 5 President George W. Bush concurrently launched the National Smallpox Vaccination Program, a campaign aimed at voluntarily vaccinating 500 000 health care workers and first responders against smallpox to ensure a protected workforce in case of an intentional release of the virus. This program also used Dryvax, a previously manufactured, calf lymph-derived New York City Board of Health (NYCBOH) vaccinia virus.Reference Casey, Iskander and Roper 6 Similar to all smallpox vaccines, those used in the campaign were based on strains of vaccinia, an orthopox virus with established cross-protection to smallpox. The uptake of vaccination by health care workers was much lower than expected (38 885 total vaccinees) due to widespread reporting of severe adverse events associated with the traditional replicating vaccines, a perceived lack of liability protection in the event of vaccinia transmission to patients, and a lack of support from public health communities throughout the country.
Severe adverse events associated with traditional replicating smallpox vaccine are generally considered more dangerous than adverse events associated with other vaccines. Throughout the course of the National Smallpox Vaccination Program, the vaccine adverse event reporting system (VAERS), a national vaccine safety surveillance program cosponsored by the Centers for Disease Control and Prevention (CDC) and the FDA, received 822 reports of adverse events following vaccination (overall reporting rate, 217/10 000 vaccinees). Of these, 100 adverse events (12%) were designated as serious, resulting in 85 hospitalizations, 2 permanent disabilities, 10 life-threatening illnesses, and 3 deaths. Also, 21 cases were classified as myocarditis and/or pericarditis, in addition to 2 cases of generalized vaccinia and 1 case of postvaccinial encephalitis. In addition, 10 ischemic cardiac events (unanticipated based on historical data) were documented.Reference Casey, Iskander and Roper 6
Serious adverse events, in general, were more common among older repeated vaccinees than younger first-time vaccinees. More than half of the population vaccinated were repeated vaccinees and thus not reflective of the general US population. This finding ran contrary to the expectation that replicating smallpox vaccines would generate fewer side effects in repeated vaccinees. While the 3 reported deaths resulted from myocardial infarctions occurring after vaccination, it is unclear whether the relationship to smallpox vaccination was causal, given that a similar number of deaths due to myocardial infarction would be expected in any demographically similar population.
In spite of these setbacks, preparedness efforts subsequently shifted to ensuring a sufficient vaccine stockpile for the entire US population and maintenance of ongoing production capabilities (warm-base capability). Former Secretary of Health and Human Services (HHS) Tommy Thompson issued a directive for the US government to stockpile enough smallpox vaccine to vaccinate every person in the United States (300 million regimens). The US government has stated its smallpox medical countermeasures requirements as follows 7 :
-
∙ Replicating smallpox vaccine: sufficient quantity to protect the entire US population after a declared outbreak (300 million courses). This requirement was set by the Secretary of HHS in 2002.
-
∙ Vaccinia immune globulin: sufficient quantity to treat 30 000 people who may experience adverse reactions from traditional (live vaccinia-based) smallpox vaccination. This requirement was set by the CDC in 2002 and endorsed by the Public Health Emergency Medical Countermeasures Enterprise (PHEMCE, an interagency coordinating body) on its formation in 2006.
-
∙ Nonreplicating smallpox vaccine: sufficient quantity to protect 66 million people, including those for whom smallpox vaccine is contraindicated and their household contacts (includes 10 million immunocompromised and 28 million atopic dermatitis patients). This requirement was set by the Homeland Security Council in 2003 and endorsed by the PHEMCE in 2006.
-
∙ Antivirals: sufficient quantity of orally formulated antivirals to treat 1.7 million people with symptomatic smallpox disease. This requirement was set by the PHEMCE 2008.
Scale and Nature of the Response
In the event of an intentional or accidental release of smallpox in the United States, health experts fear that the disease could kill as many as 30% of those infected and spread rapidly due to the contagious nature of the disease, based on historical data from previous outbreaks.Reference Henderson, Inglesby and Bartlett 8 Vaccination with live, replicating vaccine (and containment) remains the US government’s primary response strategy to prevent disease and its transmission among the general population by building “herd immunity,” the immunization of a critical threshold of the population to prevent further spread.
A national smallpox response must balance the utility of replicating vaccine in preventing morbidity and mortality with the well-known, vaccine-dependent adverse events that will accompany any domestic vaccination program. The scale of the response is thus the single-most important decision facing government leaders.
The scale of the response will depend on available information about the initial event outbreak as well as real-time information about new or suspected cases. Information will be gathered using existing surveillance capabilities to ensure rapid case identification, readily identifiable due to the unique rash, coupled with contact tracing.Reference Fenner, Henderson, Arita, Jezek and Ladnyi 9 The nature of the response will likely change as epidemiological data become available. A smallpox vaccine response will range from vaccination for specific groups or localities to nationwide mass vaccination. Presumably, there will be pressure toward universal nationwide vaccination if and when smallpox virus has been identified. Effective and consistent public messaging and education about the risks and benefits of available vaccines will also affect the scale of the response.
Smallpox Vaccine Prioritization and Allocation
Vaccination with vaccinia-based vaccines to build herd immunity and break the chain of infection should be the primary response strategy for the general population in the event of an outbreak. Although the antiviral tecovirimat (Arestvyr, formerly known as ST-246, SIGA Technologies, Inc) has also been stockpiled in small quantities, it is not a replacement for vaccination and will be used only to treat those who contract smallpox. The use of vaccine should be based on the scope of the outbreak and targeted to maximize protection against disease while minimizing vaccine-related adverse events.
The smallpox vaccines housed within the SNS include traditional replicating and nonreplicating smallpox vaccines. The replicating vaccines are based on strains of vaccinia virus that are administered using a bifurcated needle to create a local viral infection. Viral replication results in the formation of a pustule within a week, and formation of this vaccination lesion (or “take”) is associated with a protective response against smallpox. The available nonreplicating vaccine is based on a closely related orthopox virus that induces similar levels of immunity but without the production of a take.
Replicating Vaccines
ACAM2000
ACAM2000 is licensed by the FDA for active immunization against smallpox disease for persons at high risk for smallpox infection. It is the primary vaccine in response to a smallpox emergency. Current supplies of ACAM2000 are sufficient to vaccinate the majority of the US population. 10 Replicating vaccines are highly effective when used as pre-exposure prophylaxis (estimated >95%), with peak immune response reached 28 days after vaccination.Reference Breman and Henderson 11 The CDC estimates that vaccination within 3 days of exposure will completely prevent or significantly modify smallpox in most people; vaccination 4 to 7 days after exposure likely offers some protection from disease or may modify its severity. 12 After that, vaccine efficacy is largely negligible. ACAM2000 must be administered by vaccine providers with training to safely and effectively administer the vaccine by the percutaneous route (scarification) using 15 jabs of a bifurcated needle. ACAM2000 is contraindicated for individuals with severe immunodeficiency who are not expected to benefit from the vaccine, 13 which may include persons who are undergoing bone marrow transplantation or those with primary or acquired immunodeficiency states who require isolation.
ACAM2000 has a boxed warning, which states that suspect cases of myo- and pericarditis were observed at a rate of 5.7 per 1000 primary vaccinees (95% CI: 1.9-13.3). Also, ACAM2000 administration may lead to a range of other conditions associated with serious morbidity and mortality, including various encephalopathies, progressive vaccinia, generalized vaccinia, erythema multiforme major, eczema vaccinatum, ocular complications, and fetal death. These risks are increased in certain individuals, including people who have eczema or atopic dermatitis; people with weakened immune systems, such as those who have received a transplant, are HIV positive, or are receiving treatment for cancer; women who are pregnant or breastfeeding; and children under 1 year of age. 14 These adverse effects may result in severe disability, permanent neurological sequelae, and/or death. Health complications have occurred after either primary vaccination or revaccination with replicating smallpox vaccines. The vaccination lesion is also infectious until the scab separates 3 to 4 weeks after the onset of the rash, posing a risk to close contacts and vaccinees themselves through unintentional self-inoculation.
APSV
Aventis Pasteur smallpox vaccine (APSV), also known as Wetvax, is the liquid preparation of the live-virus vaccine derived from the NYCBOH strain. Produced in 1958 and grown on calf skin, Wetvax is available as a liquid virus suspension in a glycerinated diluent (not lyophilized). It is intended as a backup vaccine if supplies of ACAM2000 run out. APSV can be used only subject to the terms and conditions of an Emergency Use Authorization, which allows the FDA commissioner to permit use of unapproved medical products or unapproved uses of approved products in an emergency (21 USC §360bbb-3 [2013]). As a replicating strain, it is potentially subject to the same types of complications observed with ACAM2000.
Nonreplicating Vaccine
IMVAMUNE
IMVAMUNE, whose active substance is Modified Vaccinia Ankara-Bavarian Nordic (MVA-BN, Bavarian Nordic), is available for emergency use in the SNS as an unlicensed vaccine. In 2013, the vaccine was licensed by Health Canada and by the European Medicines Agency (as IMVANEX). In the event of a smallpox outbreak, it is likely that IMVAMUNE would be administered in the United States under an Emergency Use Authorization, which would allow the vaccine to be used in a public health emergency to protect individuals of all ages with immunosuppression as a result of HIV infection or with atopic dermatitis, including children, pregnant women, and nursing mothers.
IMVAMUNE is administered through subcutaneous injection and induces levels of Variola-neutralizing antibodies similar to a standard Dryvax vaccination 14 days after the completion of a 2-dose vaccination schedule (day 0 and day 28).Reference Damon, Davidson and Hughes 15 , Reference Vollmar, Arndtz and Eckl 16 Currently, IMVAMUNE has been administered to more than 7500 people (personal communication, Nathaly Arndtz-Weidemann) including 1000 people diagnosed with atopic dermatitis or infected with HIV, without safety concerns.Reference Kennedy and Greenberg 17 Licensure by the European Medicines Agency included an assessment of 13 completed clinical trials covering 3432 of these individuals.Reference Kennedy and Greenberg 17 , 18 The absence of an infected vaccination lesion and the replication-deficient nature of the vaccine mitigate the risk of infection to contacts or unintentional self-inoculation of vaccinees.
Decisions regarding smallpox vaccine prioritization and allocation must be based on shifting epidemiological, scientific, and political variables. As such, it is difficult if not impossible to definitively predict decisions on medical countermeasures allocation. Senior government leaders must determine the prioritization or circumstances in which individuals will receive the vaccines described. According to the National Response Framework, Emergency Support Function No. 8 (Public Health and Medical Services annex), the primary response agency during a smallpox response will be HHS and its leadership, with support from various federal agencies that include but are not limited to the DoD, Department of Agriculture, DHS, and Department of Justice. If government leaders decide on a mass vaccination strategy, the monitoring of adverse events from ACAM2000 and APSV will be of utmost importance in determining how best to use limited supplies of IMVAMUNE, for example. However, to the extent possible, the federal government should exercise a tiered vaccination approach, which will likely separate into 4 potentially overlapping categories:
-
∙ Post-event/pre-exposure prophylaxis of health care workers and other critical personnel;
-
∙ Ring vaccination;
-
∙ Mass local vaccination; and
-
∙ National mass vaccination.
Post-Event/Pre-Exposure Prophylaxis of Health Care Workers and Other Critical Personnel
In the event that smallpox is confirmed outside of the United States, pre-exposure vaccination should be recommended for health care workers and, potentially, for other federal, state, and local emergency responders and critical infrastructure personnel. Vaccination of health care workers will be essential to ensure that adequately protected medical and public health personnel are available to manage and contain the spread of an outbreak. Vaccination of federal, state, and local emergency responders and critical infrastructure personnel will likely be required to ensure that these individuals are willing and able to continue to perform essential services in an outbreak scenario.
ACAM2000 should be recommended for each of these groups, with the exception of those eligible for IMVAMUNE (individuals with HIV and atopic dermatitis). It is important to note, however, that during the 2002 civilian smallpox vaccination program these groups were hesitant to be vaccinated with the replicating vaccine due to fears of severe adverse events and the risk of transmission of vaccinia virus from vaccinees to close contacts (including patients) through inadvertent contact with the vaccination site. In addition, health care providers who receive replicating vaccine must be particularly cautious as they could infect close contacts for 2 to 3 weeks after vaccination.
Ring Vaccination
In the event that smallpox spreads to the United States but is restricted to 1 or a few cases, ring vaccination, in which direct contacts of diagnosed cases are identified, monitored, and/or vaccinated to prevent the spread of the disease, should constitute the primary strategy for breaking the chain of transmission. ACAM2000 should be the first line of defense, with IMVAMUNE offered to individuals with HIV and atopic dermatitis in the affected area.
Mass Local Vaccination
If the outbreak spreads but remains in a single location, ring vaccination with ACAM2000 should remain the primary strategy to break the chain of transmission. However, given the high percentage of the US population that is HIV positive or has atopic dermatitis, up to 25% of the population (>78 million individuals) would have to be excluded from ACAM2000 vaccination when household contacts are included.Reference Kemper, Davis and Freed 19 – Reference Naleway, Belongia and Greenlee 21 It is increasingly likely, therefore, that supplies of IMVAMUNE would be insufficient. As a result, only individuals with HIV and atopic dermatitis at the highest risk for serious and life-threatening, replication-dependent complications associated with ACAM2000 should be given access to IMVAMUNE.
Other high-risk individuals, such as those receiving immunosuppressive drugs (for disorders such as rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus), as well as individuals who have received transplanted organs, should only be given replicating smallpox vaccine if deemed at high risk for smallpox exposure. Severe adverse events and monitoring efforts associated with traditional replicating vaccinia vaccines will continue to stress the public health system locally and at a national level.
National Mass Vaccination
In the event that the disease spreads throughout the United States or that surveillance capabilities are unable to identify cases and contacts quickly enough to stem the epidemic using ring vaccination and contact tracing, nationwide vaccination will be recommended. If this occurs, ACAM2000 should be offered to the majority of the population, with APSV as needed. As in the previous scenario, IMVAMUNE should be given to indicated individuals at highest risk of serious and life-threatening replication-dependent vaccine complications. Stockpiles of IMVAMUNE will diminish rapidly, in spite of vaccine prioritization efforts. Severe adverse events associated with traditional replicating vaccinia vaccines will mount rapidly, testing the limits of the public health system and medical system and resulting in significant morbidity and mortality throughout the population.
Using the city of Atlanta, Georgia (population ∼5500000), as an example, it is feasible that roughly 110 000 individuals will suffer from some form of adverse event associated with traditional replicating vaccines. Using data from the 2002 civilian smallpox program, in which 2% of vaccinees suffered adverse events, and 0.3% of vaccines suffered serious adverse events, 16 500 individuals in the hypothetical Atlanta scenario could develop serious adverse events.Reference Casey, Iskander and Roper 6 Monitoring for severe adverse events will become increasingly difficult (if not impossible) due to limited resources.
These scenarios require senior government leaders to grapple with 2 challenging vaccine prioritization issues. First, it will be essential that health care workers and other critical infrastructure personnel be encouraged to avail themselves of vaccination. It is possible that members of the health care community will seek access to the nonreplicating IMVAMUNE vaccine, especially if the risk of localized outbreak is perceived as low. Carefully balancing the need to encourage high levels of health care worker participation in post-event but pre-exposure vaccination programs will be critical and may conflict with a desire to limit the distribution of nonreplicating vaccines in the early stages of a smallpox outbreak. Second, officials may have to decide how to make smallpox vaccines available on a voluntary basis for worried citizens who wish to protect themselves and/or their families but who may fall outside of the specific vaccine-prioritization tiers. Communicating the risk associated with available smallpox vaccines and the national need to prioritize how limited resources are made available will be essential elements to a successful smallpox outbreak response.
Nonvaccine Poxvirus Countermeasures
An antiviral for smallpox, Arestvyr, is currently in late-stage clinical development and is available for emergency use in the SNS. In 3 clinical trials (phases I and II) to evaluate the safety, tolerability, and pharmacokinetics of Arestvyr, no serious adverse events were reported (total enrollment of 149 health individuals, aged 18-75 years).Reference Grosenbach, Jordan and Hruby 22 The FDA has placed Arestvyr on “fast-track” status, creating a path for expedited review and regulatory approval. Antivirals are not expected to replace vaccines but are intended for the treatment of symptomatic patients who can no longer benefit from vaccination (eg, individuals exposed to smallpox more than 7 days before and who received no vaccine).
Vaccinia immune globulin intravenous (VIGIV, Emergent Biosolutions) is also available in the SNS for the treatment of complications resulting from replicating smallpox vaccination for both vaccinees and their contacts. VIGIV is administered intravenously only, and is not particularly amenable to the high patient throughput necessitated by a mass vaccination campaign. Moreover, limited data exist on the efficacy of treating severe adverse events with VIGIV. Finally, VIGIV’s per unit acquisition cost and annual life cycle cost per regimen are also quite high.
Conclusions
Vaccination to build herd immunity and break the chain of infection must be the primary response strategy for the general population in the event of a smallpox outbreak. Smallpox vaccines could also prove useful in the case of other poxvirus outbreaks such as monkeypox. The replicating vaccine ACAM2000 should be the primary countermeasure available for the general population. The nonreplicating vaccine IMVAMUNE should be given to indicated individuals at risk of serious and life-threatening replication-dependent vaccine complications. As a result, significant numbers of severe adverse events associated with traditional replicating vaccines should be anticipated in the event of a smallpox outbreak.
These severe adverse events will present significant practical, logistical, and ethical challenges for the public health system and will result in significant morbidity and mortality throughout the population. VIGIV is not anticipated to significantly mitigate these severe adverse events. The antiviral Arestvyr will be used to treat individuals with smallpox who can no longer benefit from vaccination. However, stockpile availability of this treatment will be minimal, and this product will be a last line of defense only for individuals showing smallpox disease.
Nevertheless, well-considered and science-based decisions regarding the use and allocation of smallpox vaccines and other non-vaccine poxvirus countermeasures are critical to US health security and must be made using the best information available. At every step of a public health response to a smallpox outbreak, senior government leaders will be forced to weigh scientific, epidemiological, and political realities and make difficult choices to reduce morbidity, mortality, and public unease.
Successful vaccination campaigns must strive to balance public demand for vaccine versus the risk of severe adverse events from traditional replicating vaccines. Given the prevalence of HIV and atopic dermatitis in the United States, maintaining a stockpile of nonreplicating vaccine to supplement traditional vaccine stockpiles remains critical. Successful vaccination campaigns will also fundamentally depend on frequent, concise, and clear communication with the public regarding the risks and benefits of available smallpox countermeasures.
Funding and Support
This work was supported by Bavarian Nordic.
Acknowledgment
Ellen P. Carlin of Carlin Communications, LLC provided technical assistance in the drafting of the manuscript.
