Smallpox, an infectious disease unique to humans, is believed to have emerged in human populations about 10,000 BC. The virus localized in small blood vessels of the skin, mouth, and throat. In the skin, it resulted in a characteristic maculopapular rash and, later, raised fluid-filled blisters.
Of the two forms of the virus, Variola major produced a more serious disease with an overall mortality rate of 10-15% in adults and 80% in children. Variola minor caused a milder form of the disease, with a death rate around 1-2%. Long-term complications of V. major infection were primarily the characteristic scars, commonly on the face. While millions have reportedly died from smallpox, the CDC has admitted that the actual cause of death is “a mystery.”
The last reported case of smallpox in the U.S. was in Texas in 1941. The last case worldwide was in Ethiopia in 1972. While the WHO and CDC give credit for the eradication to a global smallpox vaccination campaign, many sources site viral burn out and an increase in global refrigeration and sanitation the actual cause for the elimination of smallpox from the general population.
ACAM2000® Package Insert Cdc-pdf[PDF – 11 pages ]External
Medication Guide, ACAM2000® Cdc-pdf[PDF – 6 pages]External
Use of Vaccinia Virus Smallpox Vaccine in Laboratory and Health Care Personnel at Risk for Occupational Exposure to Orthopoxviruses – Recommendations of the Advisory Committee on Immunization Practices (ACIP), 2015 Source: MMWR 2016, 65(10);257–262. “ACAM2000 is a vaccinia virus vaccine derived from a plaque-purified clone of the same New York City Board of Health strain that was used to manufacture Dryvax vaccine. ACAM2000 is grown in African green monkey kidney (Vero) cells and tested to be free of known adventitious agents. Safety data from ACAM2000 clinical trials indicate a similar safety profile to Dryvax, including a risk for serious adverse events (e.g., progressive vaccinia, postvaccinial encephalitis, and eczema vaccinatum). Myopericarditis has also been associated with ACAM2000 and is estimated to occur at a rate of 5.7 per 1,000 primary vaccinees based on clinical trial data.
Smallpox Vaccination and Adverse Reactions: Guidance for Clinicians Source: MMWR 2003, 52(RR04);1-28.
Clinical Guidelines for Smallpox Vaccine Use in a Postevent Vaccination Program Source: MMWR 2015, 64(RR02);1-26.
Medical Management of Adverse Reactions
Vaccines, Blood & Biologics ACAM2000 STN: BL 125158 Proper Name: Smallpox (Vaccinia) Vaccine, Live Tradename: ACAM2000 Manufacturer: Sanofi Pasteur Biologics Co., License No. 1815 Indication: Active immunization against smallpox disease for persons determined to be at high risk for smallpox infection.
Vaccines, Blood & Biologics Proof-of-concept Dual Vaccine against both Smallpox and Anthrax
SLIDES AND NOTES History and Epidemiology of Global Smallpox Eradication (pdf)
May 2021 – The Brighton Collaboration standardized template for collection of key information for risk/benefit assessment of a Modified Vaccinia Ankara (MVA) vaccine platform “MVA-BN has been approved as smallpox vaccine in Europe and Canada in 2013, and as smallpox and monkeypox vaccine in the US in 2019. No signal for inflammatory cardiac disorders was identified throughout the MVA-BN development program. This is in sharp contrast to the older, replicating vaccinia smallpox vaccines, which have a known risk for myocarditis and/or pericarditis in up to 1 in 200 vaccinees. MVA-BN-Filo as part of a heterologous Ebola vaccination regimen (Ad26.ZEBOV/MVA-BN-Filo) has undergone clinical testing including Phase III in West Africa and is currently in use in large scale vaccination studies in Central African countries. This paper provides a comprehensive picture of the MVA-BN vector, which has reached regulatory approvals, both as MVA-BN backbone for smallpox/monkeypox, as well as for the MVA-BN-Filo construct as part of an Ebola vaccination regimen, and therefore aims to provide solutions to prevent disease from high-consequence human pathogens.”
December 21, 2020 – MVA-BN as monkeypox vaccine for healthy and immunocompromised “Conclusion: MVA-BN was immunogenic and reached levels considered protective in both macaques and humans. FDA approved MVA-BN (September 2019) for use in adults aged ≥18 years (including immune compromised individuals) at high risk for smallpox or MPX infection.
September 24, 2019 – FDA approves first live, non-replicating vaccine to prevent smallpox and monkeypox “The U.S. Food and Drug Administration announced today the approval of Jynneos Smallpox and Monkeypox Vaccine, Live, Non-Replicating, for the prevention of smallpox and monkeypox disease in adults 18 years of age and older determined to be at high risk for smallpox or monkeypox infection.”
September 3, 2019 – HHS Purchases Smallpox Vaccine to Enhance Biodefense Preparedness “As part of ongoing preparedness efforts against biodefense threats, the U.S. Department of Health and Human Services (HHS) will purchase smallpox vaccine, called ACAM2000, to build and replenish vaccine stored in the Strategic National Stockpile (SNS) over the next decade.”
February 2019 – Atypical Cowpox Virus Infection in Smallpox-Vaccinated Patient, France “We isolated a cowpox virus from the lesions and sequenced its whole genome. The patient reported that he had been previously vaccinated against smallpox. We describe an alternative route of cowpox virus infection and raise questions about the immunological status of smallpox-vaccinated patients for circulating orthopoxviruses.”
January 2019 – 537: Severe Encephalitis After Primary Smallpox Vaccination
September 2018 – Acral papulovesicular eruption after smallpox vaccination: 6757 “Acral papulovesicular eruption is a distinct presentation which has been described in U.S. military members following vaccination with the second generation smallpox vaccine ACAM2000. We characterize this unique eruption with 12 reported cases so far, as well as review previously described cutaneous adverse events associated with smallpox vaccination.
April 2018 – Influence of Population Immunosuppression and Past Vaccination on Smallpox Reemergence “Persons born after 1980 have no immunity to smallpox because they have never been exposed to wild-type virus or been vaccinated. For vaccinated cohorts, immunity wanes over time, and the highest protection is present during the first 5 years after vaccination, possibly waning to zero within 5–10 years. Comment: The vaccine that is supposed to last forever.
December 19, 2017 – Equination (inoculation of horsepox): An early alternative to vaccination (inoculation of cowpox) and the potential role of horsepox virus in the origin of the smallpox vaccine “It has been said that after publishing the Inquiry, Jenner abandoned the hypothesis of the horse origin of the preventative against smallpox. In fact, in his subsequent works about the smallpox vaccine, published between 1779 and 1801, Jenner did not make any explicit reference to the potential horse origin of cowpox. The reality is that although in public Jenner downplayed a potential role of grease, probably to avoid unnecessary distractions from his main findings, in private he continued favoring the possibility that horse grease could also be a preventative of smallpox.
October 12, 2017 – An Early American Smallpox Vaccine Based on Horsepox “The results of our analysis of this 1902 smallpox vaccine provide evidence of the suspected role of horsebox in the origin of the smallpox vaccine, a role that was suspected even by Jenner himself.2 In fact, during the 19th century, inocula derived from cowpox or horsebox were used interchangeably to immunize against smallpox. The origin of the Mulford 1902 vaccine stock is unknown, but it was probably obtained from Europe because horsepox was absent from the Americas. The identification of a link between 19th-century and modern smallpox vaccines strengthens the hypothesis that the horsepox virus may be the ancestor of the vaccinia lineage.”
October 5, 2015 – Sex difference in immune response to vaccination: A participant-level meta-analysis of randomized trials of IMVAMUNE® smallpox vaccine “Our results show statistically significant differences in response to IMVAMUNE comparing healthy, vaccinia-naïve men with women and suggest that sex should be considered in further development and deployment of IMVAMUNE and other MVA-based vaccines.
August 26, 2015 – Analysis of pregnancy and infant health outcomes among women in the National Smallpox Vaccine in Pregnancy Registry who received Anthrax Vaccine Adsorbed ”
August 2015 (Expedited Ahead-of-Print Articles) – Smallpox Vaccination of Laboratory Workers at US Variola Testing Sites (full text) “Most barriers to revaccination were related to medical conditions (compromised immunity and/or exfoliative skin disorders) that place vaccinees at high risk for adverse events to the currently licensed smallpox vaccine. The conditions are an added challenge for the aging pool of laboratory workers assigned to national variola testing sites. Currently, unlicensed third-generation smallpox vaccines may be considered (pending licensure) as replacements to ACAM2000 (Sanofi Pasteur Biologics, Lyon, France), the currently licensed vaccinia vaccine, for laboratory workers at national variola testing sites or perhaps an even broader population of laboratory workers throughout the United States. Third-generation vaccines are nonreplicating and safer in populations that might have contraindications to traditional vaccines.”
June 12, 2015 – Smallpox vaccine, ACAM2000: Sites and duration of viral shedding and effect of povidone iodine on scarification site shedding and immune response “Autoinoculations and secondary and tertiary transmissions due to VACV shedding from the vaccination site continue to occur despite education of vaccinees on the risks of such infections.”
July 26, 2014 – Anthrax and smallpox errors highlight gaps in US biosafety “Unfortunately, this was not an isolated incident. The CDC report listed four similar incidents in the past decade in which dangerous pathogens were mistakenly sent to other laboratories. In 2006, BRRAT accidentally sent viable B anthracis DNA to two external laboratories, and another CDC laboratory accidentally sent out live botulism bacteria. In 2009, it was discovered that a strain of brucella that the CDC had been sending out since at least 2001 was not the attenuated vaccine strain as had been thought. And just before the report was published the CDC learned that in March this year a strain of low-pathogenic avian flu was accidentally cross-contaminated with highly pathogenic H5N1 before being sent to a US laboratory.” Comment do you trust the CDC with vaccines for your loved one?
October 28, 2013 – Evaluating the efficacy and safety of CJ smallpox vaccine “Although 95.9% (139/145) reported adverse events related to vaccination, no serious adverse reactions were observed.”
October 2013 – Race and sex-based differences in cytokine immune responses to smallpox vaccine in healthy individuals (full text) “These data suggest that vaccinia-specific cytokine responses following primary smallpox vaccination are significantly influenced by race and sex of vaccinees.”
July/August 2013 – Transcriptomic profiles of high and low antibody responders to smallpox vaccine “We also identified a small number of genes that exhibited significantly different expression profiles in subjects with robust humoral immunity compared with those with weaker humoral responses. Our results provide evidence that differential gene regulation patterns may be at work in individuals with robust humoral immunity compared with those with weaker humoral immune responses.”
Volume 9, Issue 7 2013 – Unintentional transfer of vaccinia virus associated with smallpox vaccines: ACAM2000® compared with Dryvax® “We identified 309 reports for ACAM2000® with skin or ocular involvement, of which 93 were autoinoculation cases and 20 were contact transmission cases. The rate for reported cases of autoinoculation was 20.6 per 100,000 vaccinations and for contact transmission was 4.4 per 100,000 vaccinations. Eighteen contact transmission cases could be attributed to contact during a sporting activity (45%) or intimate contact (45%). Of the 113 unintentional transfer cases, 6 met the case definition for ocular vaccinia. The most common locations for all autoinoculation and contact cases were arm/elbow/shoulder (35/113; 31%) and face (24/113; 21%).”
October 19, 2012 – Estimated size of the population at risk of severe adverse events after smallpox vaccination in Israel “Approximately 4.3% of the Israeli population should not be exposed to the currently used smallpox vaccine. This knowledge is important to ensure the effectiveness of mass vaccination programs in the event of a bioterror attack.”
October 2012 – The Contribution of Residents Who Cooperate With Ring-Vaccination Measures Against Smallpox Epidemic “Methods: A discrete-time, stochastic, individual-based model was used to simulate the spread of a smallpox epidemic that has become a more pressing topic due to 9/11 and to assess the effectiveness of and required resources for ring-vaccination measures in a closed community. In the simulation, we related sensitive tracing to the level of activity of the public health agency and strict isolation to the level of voluntary cooperation from residents. Results: Our results suggest that early and intensive case detection and contact tracing by public health agencies can reduce the scale of an epidemic and use fewer total resources. In contrast, voluntary reporting by the traced contacts of symptom onset after vaccination had little impact on the scale of epidemic in our model. However, it reduced the total required resources, indicating that citizens’ voluntary cooperation would contribute to reducing the burden on public health agencies.”
September 4, 2012 – High dimensional gene expression profiling studies in high and low responders to primary smallpox vaccination “We identified novel and known immunity-related genes and pathways that may account for differences in immune response to smallpox vaccination.”
July 3, 2012 – Title: Purification of vaccinia virus- and recombinant vaccinia virus-based vaccines (patent) “Vaccinia Viruses-based vaccines have in general been manufactured in primary CEF (Chicken Embryo Fibroblasts) cultures. Vaccines manufactured in primary CEF cultures are generally considered safe as regards residual contaminants. First, it is scientifically unlikely that primary cell cultures from healthy chicken embryos should contain any harmful contaminants (proteins, DNA). Second, millions of people have been vaccinated with vaccines manufactured on CEF cultures without any adverse effects resulting from the contaminants (CEF proteins and CEF DNA). There is, therefore, no regulatory requirement for the level of host cell contaminants in vaccines manufactured in primary CEF cultures, but for each vaccine the manufacturer must document its safety. The regulatory concern for vaccines manufactured in primary CEF cultures relates to the risk of adventitious agents (microorganisms (including bacteria, fungi, mycoplasma/spiroplasma, mycobacteria, rickettsia, viruses, protozoa, parasites, TSE agent) that are inadvertently introduced into the production of a biological product).”
June 18, 2012 – A single cidofovir treatment rescues animals at progressive stages of lethal orthopoxvirus disease “Irrespective of treatment dose, all surviving animals developed a protective immune response even when the CDV treatment was initiated one day p.e.. After seven days post treatment with the highest dose (100 mg/kg), virus was still detected in some organs (e.g. lung and liver) yet all animals survived, suggesting that efficacious single CDV treatment requires a potent immune system. The combination of CDV and vaccination provided no additional protection over CDV alone.”
March 9, 2012 – In Vitro Characterization of a Nineteenth-Century Therapy for Smallpox ”
March 1, 2012 – Critical Role of Perforin-dependent CD8+ T Cell Immunity for Rapid Protective Vaccination in a Murine Model for Human Smallpox ” Rapid induction of T cell immunity might serve as a new paradigm for treatments that need to fit into a scenario of protective emergency vaccination.”
November 13, 2011 – Cost, need questioned in $433-million smallpox drug deal A company controlled by a longtime political donor gets a no-bid contract to supply an experimental remedy for a threat that may not exist. “Unlike the smallpox vaccine, which remains potent for decades, Siga’s drug is guaranteed for only 38 months. The administration had intended to award Siga the exclusive option to replenish or expand the stockpile, but officials relented after Chimerix formally protested. In June, the government settled the dispute by dropping the exclusivity provision. That limited the value of Siga’s contract to $433 million and meant that other companies could compete to fill future orders for the drug.”
November 12, 2011 – The remaining smallpox stocks: the wrong debate?
November 12, 2011 – The remaining smallpox stocks: the wrong debate? — Authors’ reply
September 16, 2011 – The Development and Evaluation of Next-Generation Smallpox Vaccines (pdf) “Obviously, this is not an ideal vaccine. In a significant number of people, it did cause a severe infection and it could actually be the start of a focus of infections.”
April 5, 2011 – How The ‘Pox’ Epidemic Changed Vaccination Rules (includes audio)
April 2010 – Alfred Russel Wallace and the Antivaccination Movement in Victorian England (full text) “I also briefly analyze the similarities and differences between the Victorian and contemporary vaccination debates. It has recently been argued that comparative historical analysis can play a major role in public health policy. In contemporary vaccination controversies, history is frequently used as a source of arguments, but the historical argument often is not based on up-to-date historical understanding. The polarizing controversies surrounding vaccination have never completely gone away, and the nearly unbroken tradition of debate apparently entices participants to reuse old arguments without making certain that their context is still valid. Vaccination involves national and international politics and the deeply personal sphere of child care. It is thus probably inevitable that culturally influenced ideas of bodily integrity and health from time to time are at odds with so-called vaccination technocracies.
March 2009 – Integrated analysis of genetic and proteomic data identifies biomarkers associated with adverse events following smallpox vaccination “Complex clinical outcomes, such as adverse reaction to vaccination, arise from the concerted interactions among the myriad components of a biological system. Therefore, comprehensive etiological models can be developed only through the integrated study of multiple types of experimental data. In this study, we apply this paradigm to high-dimensional genetic and proteomic data collected to elucidate the mechanisms underlying the development of adverse events (AEs) in patients after smallpox vaccination.”
December 2008 – Post-vaccination encephalomyelitis: literature review and illustrative case.
November 2006 – Neurologic adverse events associated with smallpox vaccination in the United States – response and comment on reporting of headaches as adverse events after smallpox vaccination among military and civilian personnel (full text) “Given our observation that military samples, whether using active or passive reporting of adverse events following smallpox vaccination, tend to report fewer adverse events than civilian samples, their process of combining a relatively small civilian sample with a far larger military sample is also probably suspect in terms of generating accurate rates of adverse events, even if the numbers of civilian and military vaccines had been correct or were to be adjusted to correct values. The publishing of such uncorrected errors and weak methodologies by officials, most of whom are employed full-time by the U.S. government and/or the U.S. military, in pre-eminent medical journals, such as JAMA, does not contribute to public trust in the U.S. government’s current approach to vaccination programs that were designed by public policy and law, at taxpayer expense, to support international efforts to counter the threat of bioterrorism.”
July-September 2005 – The Value of Vaccination (full text) “You let a doctor take a dainty, helpless baby, and put that stuff from a cow,which has been scratched and had dirt rubbed into her wound, into that child. Even, the Jennerians now admit that infant vaccination spreads disease among children. More mites die from vaccination than from the disease they are supposed to be inoculated against.” (George Bernard Shaw, 1929)
May 2004 – The Bradford smallpox outbreak in 1962: a personal account “Unfortunately 3 children died after clinical diagnosis of post-vaccinal encephalitis, although the post mortems in each case showed only cerebral oedema and congestion and the pathologist could only go as far as to conclude‘ cerebral congestion following vaccination’. One of the three was of considerable interest. The child, aged 1½ years, had not been vaccinated because of an infected nappy rash, but had been bathed with her sister who had been vaccinated. She developed multiple skin lesions from which vaccinia virus was subsequently recovered at post mortem. The brain showed congestion.”
June 25, 2003 – Myopericarditis Following Smallpox Vaccination Among Vaccinia-Naive US Military Personnel “Myopericarditis should be considered an expected adverse event associated with smallpox vaccination. Clinicians should consider myopericarditis in the differential diagnosis of patients presenting with chest pain 4 to 30 days following smallpox vaccination and be aware of the implications as well as the need to report this potential adverse advent.”
April 22, 2003 – Smallpox and smallpox vaccination Neurological implications “Among the most serious complications is postvaccinal encephalomyelitis (PVEM). A related condition, postvaccinial encephalopathy (PVE), may be seen in children less than two years of age. There are no markers to predict who will develop PVEM. In the past, mortality was high, ranging from 10 to 50%. The neuropathology of PVEM suggested an immune-mediated attack on the CNS, but the target of the immune response is unknown.”
August 2000 – ‘Bacilli and Bullets’:: William Osler and the Antivaccination Movement
1996 – Universal hepatitis B Vaccination: Is it a Sword of Damocles Hanging Over the Head of the American People? “In 1973, Adams, et al, reported a case of severe demyelinization occurring years after primary smallpox vaccination. This report and that of Wells lend doubt regarding the efficacy of surveillance after viral vaccinations that only takes into account reactions occurring a few weeks after vaccination.”
1972 – Necropsy findings in a case of progressive vaccinia (pdf) Progressive vaccinia is a rare but often lethal complication of smallpox vaccination. In this condition the lesion at the site of the inoculation fails to heal and becomes a progressively enlarging ulcer. New satellite vesicles often appear round this ulcer and secondary vesicles, thought to be due to haematogenous spread of the virus (Kempe, 1960), may arise in mucosal surfaces and distant areas of the skin. In some cases visceral lesions have been found at necropsy. In children the commonest underlying cause of this complication is congenital hypogammaglobulinaemia (Kempe, 1960) and in adults the immunological deficiency often associated with leukaemias or lymphomas (Dixon, 1970).
October 3, 1914 – Bacilli and Bullets. (pdf) “An attack of an infectious disease so alters the body that it is no longer susceptible to another attack of the same disease; once a person has had scarlet fever, small-pox, or chicken-pox, he is not likely to have a second attack.”