Vaccinia virus, live [vaccine against variola virus]
Cross ref.: See the entries below for the one currenty FDA-approved smallpox vaccine, Dryvax, from Wyeth; a formerly approved vaccine from Aventis Pasteur/Sanofi Pasteur; and vaccines being developed and added to stockpiles for emergency use by U.S. and foreign civilians and military. See also the entries for Vaccinia Immune Globulin (VIG; VIGIV).
Description: Smallpox is a highly infectious disease caused by infection with variola virus (also known as smallpox) Smallpox vaccines have been in use for several centuries, and involve use of live vaccinia virus (cowpox virus), a poxvirus similar to variola virus but much less pathogenic, to induce a localized skin infection, resulting in long-term immunity. Besides prevention of smallpox disease, these same vaccines are also effective for post-exposure prevention of smallpox disease, if administered soon enough (within several days) after infection with variola virus.
Previously manufactured smallpox vaccines for which stocks still exist, i.e., Dryvax from Wyeth and the Aventis Pasteur (now Sanofi Pasteur) vaccine, involve vaccinia virus growth on the bellies of infected calves, with pustules harvested for live virus. These vaccines do not meet modern standards for GMP manufacture, sterility, etc. Multiple cell cultured vaccines are in various stages of development, production, and stockpiling.
Smallpox vaccines, containing live vaccinia virus, are administered into the skin by scarification (pricking/scratching) to induce a localized topical skin infection with vaccinia virus. Successful skin infection results in a characteristic pustule, termed a “take,” which leaves a characteristic pock mark or scar on the skin of vaccinated individuals. This localized infection generally induces immunity against disease from infection with related poxviruses, including variola (smallpox) virus. However, these live vaccines can infrequently cause vaccinia virus infection and disease, including severe skin and/and systemic infections.
Biological.: Both vaccinia and variola viruses are variola virus members of the Poxviridae (poxvirus) family, subfamily Chordopoxviridae, and Ortho-poxvirus genus of DNA viruses. Variola viruses traditionally have been classified as variola major and variola minor on the basis of the severity of clinical illness caused by infection. Variola virus major is highly pathogenic, causes high mortality, and is the type usually referred to when discussing smallpox vaccines. Variola virus has brick-shaped enveloped virions approximately 200 nm in diameter (about the size of a bacterial spore) with a dumbell-shaped core containing nucleic acid. Variola virus replicates in the cytoplasm of host cells, forming B-type inclusion bodies (Guarnieri bodies), unlike many other viruses which replicate in the nucleus. The genome is composed of a single, linear, double-stranded DNA loop covalently closed at each end. The average genome has 200,000 base pairs (200 kbp), and the virus is among the largest animal viruses. The genome of several strains has been completely sequenced, and efforts are under way to assess the genetic diversity of existing variola viruses and to differentiate them. Extensive common/similar immunogenic epitopes and antibody cross-neutralization occur among orthopoxviruses. This allows for the protection against smallpox by vaccination with vaccinia viruses.
Variola virus infection, much like varicella-zoster virus (chickenpox), is highly contagious and results in a characteristic pustular rash. However, smallpox has about 30% mortality rate. Prior smallpox vaccination prevents disease in most cases, and also if administered within a few days after contact with the virus. The minimum time for long-term prophylactic immunity is 14 days. Vaccination 2-3 days after exposure has generally protected against disease, the basis for use of smallpox vaccines for post-exposure prophylaxis (treatment). Mortality may be prevented by administration of vaccine as late as 4-5 days after exposure. Vaccine efficacy is largely determined by the route of exposure to variola virus, e.g., inhalation vs. skin contact. Over 95% of primary preex-posure vaccinees develop neutralizing or hemagglutination inhibition vaccinia virus antibody titers greater than or equal to 1:10. This level of protective antibodies does not last long (boosters were formerly recommended every 5-10 years). The full extent of long-term efficacy is now being further studies, with some investigators reporting that pediatric vaccination may provide some limited life-time protection.
No adequate animal model for human variola virus infection is available. This has complicated smallpox vaccine and drug development. Some nonhuman primates can be infected with variola, but the disease is less severe than in humans and is not considered equivalent to human infection. Vaccinia vaccines are generally evaluated (using surrogate markers) for efficacy in humans by their reactogenicity or “take,” defined by formation of the characteristic vaccinia virus infection lesion (pock mark) at the site of inoculation by skin abrasion. Any future approvals of smallpox vaccines will be based on animal testing and safety and immunogenicity trials (taking advantage of the FDA “animal rule” applicable to biodefense and other products that cannot be effectively tested for efficacy), using the “take” rate and induction of humoral vaccinia virus-neutralizing antibodies as the primary surrogate markers.
Smallpox vaccine is the only agent, either therapeutic or prophylactic, of any type currently available for large-scale pre- and post-exposure prevention of smallpox from variola virus exposure. In 1995 in one of the few experiments on live variola in decades, Dr. J.W. Huggins, U.S. Army Medical Institute of Infectious Diseases (USAMRIID), reported results of testing a wide variety of antiviral drugs against variola, vaccinia and monkeypox viruses. Some agents were active against smallpox but were not active against the other viruses, and other agents were active against the other viruses but not variola virus. Cidofovir, a DNA polymerase inhibitor, marketed by Gilead Sciences for treatment of cytomegalovirus (CMV) infection has shown activity in vitro against vaccinia virus infection in a murine model and has been shown able to protect monkeys against monkeypox virus. However, cidofovir, which requires intravenous injection and entails significant side effects, is not considered a candidate drug for smallpox treatment or prophylaxis, with any potential smallpox drug or vaccine requiring better safety and ease of use in the general population. These findings suggest that available and candidate experimental drugs are not effective against and likely would not control a smallpox bioterrorist/biological warfare attack, epidemic, or pandemic.
History: Smallpox has long been a major cause of disease and mortality. Prior to the essential eradication of wild-type variola virus (discussed below), smallpox is estimated to have killed 300-500 million persons in the 20th century. Attempts to vaccinate against smallpox date back to the 6th century. The first written record of variolation, the purposeful infection of the skin with variola virus (i.e., using smallpox virus, itself, not related vaccinia virus), is attributed to a Chinese Buddhist nun in the 11th century. It is widely accepted that variolation was used in ancient times in China, India and Persia. Variolation was a dangerous method of preventing smallpox. As performed during the 1700s, variolation resulted in about two deaths for every 100 people vaccinated. Variolation was tolerated/welcome at the time, because people knew that natural smallpox infection was endemic (common) and killed about 20% or more of those who contracted it.
Variolation was the best available method until the development of smallpox vaccination using vaccinia (cowpox) virus. In 1796, Edward Jenner in England inoculated a subject with vaccinia virus, and called the procedure vaccination (vacca = cow, in Latin). Jenner’s work with cowpox vaccination was the first scientific attempt to control an infectious disease by means of a deliberate, systematic inoculation, and his work laid the foundations of modern vaccinology. By the early 1800s, vaccination replaced variolation to prevent smallpox. In the U.S., several companies manufactured and marketed live vaccinia virus (smallpox) vaccines prior to the advent of federal (FDA) regulation in 1903. This apparently included a predecessor company to Wyeth, the most recent U.S. manufacturer. The basics of smallpox vaccination have changed little since Jenner.
Companies, other than those discussed in product monographs below, previously approved for Smallpox Vaccine manufacture are: Bayer Corp (Cutter Labs./Miles), Aug. 1903-June 1973; Lederle Labs., March 1937-May 1978; Massachusetts Public Health Biologic Labs., March 1917-Dec. 1976; Michigan Biologic Products Inst., March 1937-June 1985.
Smallpox was first used as a biological weapon during the French-Indian wars in the U.S. (1754-1767), with British soldiers giving American Indians blankets that had been used by smallpox patients. This resulted in epidemics, with mortality over 50% in some affected tribes.
The smallpox vaccine used in the prior Soviet Union and now in many of its spin-off countries is composed of the New York City Board of Health (NYCBH) strain of vaccinia virus, the same as used in Dryvax.
Companies.: The Department of Defense (DOD) has used DynPort Vaccine Co, LLC, now DVC LLC, as its prime contractor for recent smallpox vaccine research, development and manufacture, as part of a 10-year, $322 million contract with DynPort for bioterrorism/biological warfare defense vaccine R&D and procurement granted by the Joint Vaccine Acquisition Program (JVAP), DOD, in fall 2000. Dyn-Port was originally a joint venture of DynCorp, a defense contractor, which was merged into Computer Sciences Corp., and Porton International Ltd., a subsidiary of Beaufour Ipsen S.A., now Ipsen S.A. In Aug. 2004, CSC acquired the 49% of DynPort owned by Porton/Ipsen, with the company now a fully-owned subsidiary of CSC and renamed DVC LLC.
Status: Due to concerted worldwide vaccination efforts, wild variola virus has been eradicated (considered extinct) since the 1970s. In 1980, the World Health Organization (WHO), United Nations, declared that smallpox had been eradicated, i.e., with humans the only natural host/reservoir for the virus and with no cases reported for years, the virus was considered extinct, except for samples held in laboratories]. The only known samples of live variola virus are stored under high security in U.S. (CDC) and Russian facilities. Smallpox vaccination was halted in the early 1970s in the U.S, based on the presumption that the wild-type virus was extinct and no longer posed a threat. In the U.S. and elsewhere, those under the age of about 30 generally have not received any smallpox vaccination, while older persons generally received smallpox vaccination as infants and are presumed to have decreased or lost all immunity. Thus, essentially all persons in the U.S. (and world) are susceptible to variola virus infection (smallpox).
Variola virus is a particularly dangerous biological weapon because of its clinical and epidemiologic properties, and the near universal susceptibility of the human population. The virus can be manufactured in large quantities, stored for an extended period of time, and delivered as an infectious aerosol. With variola virus being highly infectious (including aerosol inhalation of virus shed by symptomatic infected persons), having a high mortality rate (historically, up to 30%), and with essentially the entire world population lacking effective immunity from halt of vaccination, the virus is a potentially devastating weapon that could indiscriminately kill millions, perhaps a significant portion of the human race. There currently are no antiviral drugs available for the treatment or prevention of smallpox. Previously manufactured vaccines are in short supply (worldwide, although the U.S. likely has sufficient stocks), are past their dating period, and may be largely ineffective.
In recent years, news of former Soviet Union (USSR) mass production of biological warfare or weaponized variola virus and reports that other nations (e.g., North Korea, Iran, Iraq) and terrorist groups may be retaining, have procured, and/or are developing variola virus for biological warfare or bio-terrorism uses has prompted renewed attention to the need for smallpox vaccines. As described further below and in the following monographs, efforts are underway to resurrect old supplies of vaccines and to develop more modern vaccines for protection of military personnel and the general population in case of a new outbreak of smallpox.
Only two high security biosafety level 4 (BL-4; highest level) facilities are known to be storing variola virus samples – the Centers for Disease Control (CDC) in the U.S. and the VECTOR former (or still, depending on source) biological warfare research lab in Koltsovo, Siberia, Russia. In 1986, seeing insufficient need for retention of highly pathogenic viruses for which persons no longer have immunity and concluding that recombinant clones would suffice for future research, the Ad Hoc Committee on Orthopox Virus Infections, World Health Organization (WHO), unanimously recommended that the two official stocks of virus at CDC and VECTOR be destroyed (including potential vaccine stocks). However, some intelligence experts have reported that countries, such as North Korea, Iran and Iraq, are secretly retaining virus samples. Also, even if all stocks of stored virus were to be destroyed, the virus could (theoretically) reemerge from inadvertent release from other sources, such as release from laboratories unknowingly storing virus samples or from infected bodies long buried in Arctic permafrost. Some critics of the retention of samples of live virus view destruction of its stored stocks as largely negating the utility of the virus as a weapon for terrorist or state-sponsored use, believing that the high profile destruction of the virus would make its use by others less likely, asserting that its use would be so horrific that use of the virus would result in worldwide condemnation and inability of groups/countries to attain their political or military goals. However, this presumes that terrorists, rogue states, etc., care more about public opinion than killing their enemies. In 1996, the World Health Assembly voted to postpone destruction of smallpox stocks until after its July 1999 meeting. Destruction of the known CDC and VECTOR virus samples continues to be postponed. In May 2007, WHO delayed for at least another four years any decision on when to destroy the world’s last known stockpiles of variola virus. The 60th annual World Health Assembly, the top decision-taking body of the WHO, a United Nations agency, reaffirmed a previous commitment to getting rid of the remaining stockpiles (held by the U.S. and Russia), but agreed to postpone any decision on when this should happen until its 2011 meeting.
Although the world has been free of reported smallpox for over two decades (last reported natural case in 1977), smallpox is increasingly being viewed as a potential public health threat, whether from its use for biological warfare (e.g., by a rogue state of terrorists), its inadvertent release from laboratory Biosafety Level 4 (BL4; BSL 4) containment in the few places authorized to store reference samples, or by other release of the virus, e.g., from samples potentially still stored in laboratories worldwide. With increasing concerns that samples are/will be needed for smallpox vaccine and drug R&D, it seems unlikely that existing laboratory stocks of variola virus will be destroyed.
Dr. K. Alibek, formerly with the USSR (now Russian) VECTOR biological warfare program has testified before the U.S. Congress that the Soviet Union had produced “dozens of tons of smallpox,” referring to highly virulent India strain of variola virus concentrate liquid in frozen storage, for potential biological warfare use, and that the lab had also conducted genetic engineering studies involving splicing genes from other pathogens and, possibly, vaccine-evading genes, into variola virus. His testimony is supported by undisclosed intelligence reports. Doubts that U.S.S.R., now Russian, massive stocks of virus have been totally destroyed or are properly secured have significantly contributed to fears that smallpox may be used as a weapon, particularly by terrorists, or inadvertently released. Russian officials continue to refuse to share information with U.S. scientists and refuse to answer inquiries about the whereabouts of smallpox strains and weapon stocks. Russian scientists have reported isolating variola virus antigens, but not whole viable virus, from the bodies of 19th century smallpox victims buried in frozen soil, suggesting that viable virus might be obtained or reconstructed from smallpox victims buried in permafrost decades ago. Iraqi scientists are known to have studied camelpox, a virus related to variola virus, and allegedly used this as a surrogate for variola in biological warfare R&D.
In hindsight, many are now critical of the 1991 destruction of about 200 million doses of smallpox vaccine by the World Health Organization (WHO), which decided to destroy 99% of its stockpile rather than pay about $25,000/year for continued cold storage. At the recent purchase price of $2.76/dose, this stockpile could be considered to have had a replacement value over $500 million (or be invaluable, if needed).
In Jan. 2004, CDC reported it had found chimeric variola virus samples in its cyrogenic freezers. These were created about 40 years ago by crossing/combining variola with other poxviruses. This brought attention to proposals to genetically engineer variola viruses to develop and test vaccines. For example, the U.S. Army Medical Research Institute for Infectious Diseases (USAMRIID) has proposed inserting a gene for a fluorescent green protein into variola virus, which would facilitate antiviral drug screening and vaccine testing. Other researchers want to insert variola virus genes into other viruses to develop attenuated live vaccines and/or have safer strains for vaccine testing and drug screening. With the full genome of variola virus sequenced, some are concerned that a fully recombinant virus could be constructed, although this is considered beyond current technological capabilities.
As of late 2004, the U.S. government has indicated that it anticipates spending $1.9 billion over a 10-year period to establish and maintain a stockpile of attenuated smallpox vaccines. Entries for vaccines currently being added to the biodefense stockpile are included among the monograph below.
In Oct. 2004, the National Institute of Allergy and Infectious Diseases (NIAID), NIH, granted contracts for development and manufacture of smallpox vaccines for the U.S. biodefense stockpile. Two contracts for MVA vaccines were awarded to Bavarian Nordic A/S (in collaboration with GlaxoSmithKline plc) and Acambis, Inc. (in collaboration with Baxter) totaling $177 million. MVA is a highly attenuated form of the vaccinia virus that cannot replicate in human cells. See the related entry (#541) below for further information.
In Dec. 2004, the U.S government (HHS) pledged 20 million doses of smallpox vaccine to the global stockpile managed by the World Health Organization (WHO). This is by far the largest contribution to date to the global stockpile. As planned, the WHO Smallpox Vaccine Bank will involve a physical stockpile in Geneva, Switzerland, and a virtual global stockpile of pledged vaccine stocks. The 20 million doses of vaccine pledged by the U.S. will physically remain in the U.S. Strategic National Stockpile, but will be available for the WHO to use in the event of an emergency. The types of vaccines, e.g., Dryvax, ACAM2000, etc., being placed by the federal government in this virtual federal government stockpile have not been disclosed. Vaccine would presumably be quickly dispatched to any country experiencing an outbreak of smallpox. However, a number of logistical and political problems (e.g., deciding who gets vaccine among affected and and many more concerned countries) will likely make this rather complicated in a real emergency. In Dec. 2004, the U.K. government pledged 4 million doses to the WHO Smallpox Vaccine Bank. As with the U.S. pledge, vaccine will be physically retained within the country. In Jan. 2005, WHO reported it intends to double its current physical stockpile from 5 to 10 million doses over the next few years, with other supplies held by pledging countries.
In March 2005, an Institute of Medicine (IOM), National Academy of Sciences, study criticized the government’s failed smallpox vaccination program launched in Dec. 2002. According to the IOM, CDC did not explain the rapid launch of the program, which created murky legal and financial liability issues, and the reasons for President Bush’s decision to raise the vaccination target from 20,000 to 500,000. The study recommended that the government do a better job of informing participants in future preparedness programs.
In late 2004, it was reported that Canada has also been experiencing problems with smallpox biodefense programs. In 2003, the government said delivery of 10 million doses from Aventis Pasteur Ltd. (now Sanofi Pasteur Ltd.), Canada’s largest vaccine maker, would begin in December 2003 and be placed in stockpiles throughout the country by early spring 2004. However, the company experienced problems in the manufacture and only 6.1 million doses were delivered. The Canadian government (like the U.S. and many other governments) presumes that a “ring” or “search-and-contain” vaccination strategy will provide sufficient protection of the ~32 million population of Canada.
In June 2006, final U.S. regulations were issued concerning how healthcare workers who become ill due to smallpox vaccinations can receive financial compensation. Although the regulation itself has changed little from the interim rules that had been in force since Dec. 2003, the underlying program, in many respects, appears to be a solution to a problem that does not currently exist. No healthcare worker has reported an illness related to the vaccine for more than two years, according to the CDC (although, as discussed elsewhere, the U.S. heathcare and first-responder vaccination program has been a failure).
In March 2007, the first report of eczema vaccinatum since smallpox vaccination (among the military) resumed in 2002 was reported in the U.S., presumably from Dryvax vaccination. A 28 month old child developed eczema vaccinatum after contact with his father, a soldier vaccinated with the smallpox vaccine in preparation for deployment to Iraq. The toddler was admitted to the hospital and became critically ill, with rash involving “80 percent of the child’s body.” With no follow-up or general media reports of his death, the child apparently survived.
Medical: Serious adverse effects of smallpox vaccines, resulting from vaccinia virus infection, including encephalitis and death, are generally infrequent. A short-lived mild temperature elevation due to vaccinia virus infection is much more common. Recently vaccinated persons can transmit live vaccinia virus to non-vaccinated persons. Those exposed to vaccinia virus, whether from vaccination or from contact with those vaccinated, can develop serious disease – meningitis or infection of the brain and nervous tissues; vaccinia necrosum, a progressive disease that starts with spreading necrosis at the site of vaccination; eczema vaccinatum, pox lesions on the skin at the vaccination site or elsewhere on the body, particularly in patients with a history of eczema; and accidental infection, or lesions when the vaccine is unintentionally transferred to the eye or mouth or other parts of the body.
By comparison with other currently marketed vaccines, smallpox vaccine has a high incidence of adverse effects (such that no company would likely get involved in vaccine manufacture and marketing without federal exemption/insurance against corporate liability).
The current official policy in the U.S. and other countries for controlling smallpox outbreaks is to rely on classic “ring vaccination,” involving vaccinating those likely to have come into contact with infected persons and those regions likely containing exposed persons. Estimates vary, but 40 million or more doses might easily be required to control an single outbreak in the U.S. In 1972, a single case of smallpox in Yugoslavia required 18 million doses of vaccine to stop the spread of disease. With modern transportation and many people likely to try to flee affected areas, some doubt the likely effectiveness of “ring vaccination” for any future outbreak/epidemic.
In late 2001, spurred by mounting concerns about potential terrorist and foreign government use of variola (smallpox) virus for biological warfare, the U.S. government decided to procure enough vaccine to vaccinate the entire U.S. population. The federal government began the contracting process to for production of new, cell cultured vaccines; and began conducting clinical testing with diluted supplies of older vaccine (Dryvax from Wyeth; see #536) to determine whether the existing stockpile could be stretched to vaccinate more people. As discussed in product entries below, the Centers for Disease Control and Prevention (CDC) and U.S. Department of Defense are separately funding development, manufacture and stockpiling of over 200 million doses new cell cultured vaccinia virus smallpox vaccines. However, these are only in early stages of clinical trials, and even though they may receive approval in within the next few years, their efficacy will not have been tested, other than in animal studies and human immunogenicity studies. The vaccines being produced by Acambis plc, ACAM1000 and ACAM2000 (not ACAM3000), for the U.S. government are derived from the same vaccine strain as Dryvax, but are grown in cell culture (as opposed to the skin of calves used for Dryvax). ACAM1000 is cultured in human MRC-5 cells, and ACAM2000 is grown in monkey Vero cells.
In 1999-2000, the total then publicly acknowledged U.S. stocks of smallpox vaccine consisted of about 7 million doses of smallpox vaccine under control of the Centers for Disease Control and Prevention and the Department of Defense. However, the situation now is very different. About 15.4 million doses of Dryvax are now known to be in strategic storage. Clinical studies have indicated that these existing Dryvax stocks could be diluted five-fold and retain adequate efficacy (see the Dryvax entry, #536), with existing Dryvax stocks capable of vaccinating over 75 million persons. In early 2002, Aventis Pasteur Inc. donated to the U.S. government over 80 million doses of three-decades old frozen smallpox vaccine (see #537). The existence of these supplies had not been previously announced. Clinical studies indicate this vaccine, like Dryvax, could also be diluted 5-fold, if needed, with this vaccine potentially capable of vaccinating 425 million persons. Thus, sufficient supplies of old vaccine are available to vaccinate the entire U.S. population, with some left over for other countries. With the expected delivery of about 200 million doses of new cell cultured vaccines in 2003, the U.S. will have stockpiles with the potential equivalent of over 700 million doses of smallpox vaccine. The newer cell cultured vaccines being delivered to the government are expected to be used first.
The U.S. government has attempted, but largely failed, to implement a program of prophylactic smallpox vaccination, starting with those most likely to be involved in responding to and investigating any smallpox outbreak. About 500,000 emergency physicians, medical and other health care workers expected to care for smallpox cases, and about 500,000 in the military were to be among the first offered the currently available vaccine (Dryvax). This vaccination program started in late 2002 and was expected to be completed by March 2003. As planned, the first phase of vaccination of up to 500,000 health care worker would be followed by vaccination of up to 500,000 “first-responders,” e.g., police, fire fighters, and other emergency and medical personnel expected to be among those exposed in an attack/outbreak. Eventually, presumably after approval of the CDC-sponsored Vero cell cultured vaccine, this vaccine might be offered to the general public.
The federal first-responders and healthcare professional vaccination effort was a failure. In Oct. 2003, CDC halted the program after only 38,549 out of a planned 450,000-500,000 U.S. health care professionals were vaccinated. CDC had shipped 291,400 doses. However, health care workers avoided vaccination. Some considered it unnecessary and/or were aware of the vaccine’s potential adverse effects. Also, in March 2003, the CDC issued a warning that several health care professionals having received vaccination (with Dryvax) experienced serious heart disease within several weeks of vaccination. At least 10 states halting their vaccination programs due to this. A major problem that caused many health care professionals to avoid vaccination was the lack of any federal liability coverage for vaccinated individuals, i.e., those developing disease, missing work, hospitalized, dying, or spreading vaccinia infection to others have no recourse for compensation. Implementation of a federal liability/compensation program will require an act of Congress.
In Dec. 2003, in a belated attempt to revive the vaccination program and prepare for emergencies, the Department of Health and Human Services (HHS) implemented the Smallpox Vaccine Injury Compensation Program passed by Congress earlier that year. Funded at $42 million, the program provides financial and medical benefits to eligible members of an HHS-approved smallpox emergency response plan who sustain certain medical injuries caused by a smallpox vaccine. Also, unvaccinated individuals injured after coming into contact with vaccinated members of an emergency response plan or with a person with whom the vaccinated person had contact may be eligible for benefits. The program also provides benefits to survivors of eligible individuals whose death resulted from a covered injury. The “Smallpox Vaccine Injury Compensation Table” outlining injuries and qualifications for compensation was published in the Aug. 27, 2003 Federal Register. However, this failed to revive the vaccination program, which was fully halted in early 2004.
The U.S. Department of Defense (DOD) has been much more successful with its own vaccination program. As of Feb. 2004, over 500,000 persons in the U.S. military had received Dryvax vaccination with negligible adverse effects and deaths (well within expectations) in this generally very healthy cohort.
With new projections about the likely wide spread of a U.S. smallpox outbreak/epidemic and new cell culture vaccine supplies becoming available in 2003, U.S. public opinion has been reported to be moving towards favoring widespread voluntary prophylactic vaccination. With sufficient popular and political support, the entire U.S. population may be offered prophylactic vaccination after approval of new cell cultured vaccines, presumably after health care professionals and first responders are vaccinated. It is likely that individual states will request and be supplied with stocks of vaccines, presumably with each controlling their use (within federal guidelines).
A number of issues make even restricted federal prophylactic smallpox vaccination programs complex. Although the government has assumed some costs, the issue of vaccine liability—who will pay, how much, and under what circumstances—if far from being fully resolved. Even with a very limited vaccination program, adverse effects would be relatively common and severe by current standards. Many persons would likely suffer serious neurological and other side effects, and a some would die from systemic vaccinia virus infection. As currently planned, all vaccinations would be voluntary, but this could rapidly change in the face of an actual outbreak, along with the institution of quarantines of large parts of the country and other restrictive measures. In case of an attack/outbreak, logistical issues would complicate any vaccination program, with massive panic and transportation problems expected after any smallpox attack/outbreak. Currently, the only approved vaccine is old stocks of Dryvax, a lyophilized live vaccinia virus vaccine originally manufactured about 30 years ago by Wyeth. Many, if not most, in the U.S. would likely receive newly-Manufactured vaccine (e.g., ACAM2000, #540).
In association with any smallpox vaccination efforts, there is a critical need for Vaccinia Immune Globulin (VIG; #788-790), the only known/proven effective treatment for systemic vaccinia virus infections. However, only about 700-800 doses of approved VIG exist in government stocks. As discussed in the VIG entries, the U.S. government has issued contracts for manufacture of new supplies. Until then, the country is largely unprepared to treat serious adverse effects to be encountered from public vaccination programs involving millions of persons.
Medical: The vaccine is administered into the skin by scarification (pricking/scratching) using a bifurcated (forked needle) holding a small amount of vaccine jabbed into the skin to induce a localized topical skin infection with vaccinia virus (which leaves a characteristic pock mark or scar on the skin of vaccinated individuals). Historically, this involves 15 quick pokes into the skin on the upper arm. The resulting localized infection generally induces immunity, both humoral and cellular hypersensitivity, providing protection against disease and death from infection with variola (smallpox) virus, when administered prior to or shortly after variola virus infection. With the primary vaccination, a papule appears at the site of vaccination on about the 2nd to 5th day. This becomes a vesicle on the 5th or 6th day, which becomes pustular, umbilicated, and surrounded by erythema and induration. The maximal area of erythema is attained between the 8th and 12th day following vaccination (usually the 10th). The erythema and swelling then subside, and a crust forms which comes off about the 14th to 21st day. At the height of this primary reaction, known as the Jennerian response, there is usually regional lymphadenopathy, and there may be systemic fever and malaise.
Serious adverse effects of smallpox vaccine (from experience with Dryvax and other live vaccinia virus vaccines), including encephalitis, are generally infrequent. Vaccinated persons can transmit live vaccinia virus to a non-vaccinated person. In the U.S. in the 1960s, two studies reported similar results, finding among 6.2 million primary vaccinations in 1963 and 5.6 million vaccinations in 1968 that the vaccine caused 54 vaccinee deaths from eczema vaccinatum in 1963 and 58 deaths in 1968, as well as 54 contact deaths in 1963 and 60 contact deaths in 1968. There were 85 deaths from accidental infection in 1963 and 142 in 1968, and 22 infection deaths through contact with vaccinees in 1963 and 44 deaths in 1968. Other studies have reported the incidence of complications, including generalized vaccinia infection, as 23.4/100,000 in those receiving primary vaccination and 1.2/100,000 receiving a booster; with progressive vaccinia infection in 10.4/100,000 receiving primary vaccination and 0.7/100,000 receiving a booster.
However, the U.S. and other developed countries now contain a much larger number and percentage of persons with suppressed immune systems, e.g., HIV/AIDS patients, cancer patients on chemotherapy and/or radiotherapy, and transplant recipients taking rejection suppressing therapeutics; and the incidence of serious adverse effects from smallpox vaccination is likely to be higher than indicated by historical data. Because of the danger of an unchecked vaccinia virus infection, these live vaccines are contraindicated in patients with immune deficiencies (e.g., AIDS, transplant recipients), patients with eczematous or exfoliative skin disorders, pregnant women, and infants. These groups would face life-and-death decisions about vaccination in case of an outbreak/epidemic.
No clinical or other experimental data are available regarding the efficacy of smallpox vaccines for prevention of infection or treatment of disease from bioterrorism/biological warfare use of variola virus. For purposes of biodefense, this lack of knowledge of the efficacy of smallpox vaccine against likely threats is compounded by the aged state of older vaccine stocks and the untested efficacy of new cell cultured vaccines.
In Dec. 2008 issue of The American Journal of Medicine, an NIAID study reported that among 249 participants of the Baltimore Longitudinal Study of Aging to gauge how long the smallpox vaccine offers protection, 209 received at least one smallpox vaccination between 13 and 88 years before the study, and researchers determined they still had antibodies from these vaccinations. The investigators concluded, " "We found that vaccinated subjects maintain what appear to be protective levels of neutralizing antibodies to vaccinia indefinitely and do not require booster vaccinations even if they are many decades removed from primary vaccination."
R&D: Research and development of any new variola virus vaccines and/or antiviral drugs are very problematic. With no validated animal models for smallpox, testing and approval will be based on safety, and “take” rate and immune responses in clinical trials in healthy volunteers. Vaccine efficacy cannot be tested in humans (unethical), since this would require exposure to live pathogenic virus and lead to outbreaks. Also, smallpox vaccine development raises a number of complex societal and political issues. How would an effective drug or vaccine be marketed Would vaccine only be stockpiled by governments and used only to vaccinate military and emergency response personnel, or would vaccine be marketed like any other approved vaccine, or given free to all Would just a few affluent countries’ governments and/or militaries receive vaccine Would vaccine be adopted again for universal worldwide vaccination Would the vaccine be restricted/controlled (and by whom) as a strategic military asset As the U.S. and other countries acquire stocks of vaccines sufficient to protect their entire population and/or military, will this be considered a hostile act (enabling that country to use variola virus as a first-strike weapon) Who will fund, control, and decide these issues in the U.S.—vaccine manufacturers, FDA, DOD, Congress, international bodies such as WHO
In Dec. 2004, the U.S. Congress passed a law (appended to a larger bill) imposing a penalty of up to 25 years in prison for attempts to engineer smallpox virus. It defines the pathogen as “a virus that can cause human smallpox or any derivative of the variola major virus that contains more than 85% of the gene sequence.” Some researchers have complained about that definition -- that it covers some pox viruses useful for vaccines.
Several companies are developing and manufacturing in large-scale new cell cultured vaccinia virus-based smallpox vaccines under U.S. government contract. See the entries for ACAM1000 (entry #539), formerly stockpiled by the Department of Defense (DOD), and ACAM2000 (entry #540), stockpiled by the Centers for Disease Control and Prevention (CDC) for non-military use.
Several companies are developing cell cultured Modified Vaccinia Ankara (MVA)-based smallpox vaccines involving use of live MVA strain vaccinia virus. MVA has decreased pathogenicity and infectivity in humans, and is initially being developed for use in the many persons, e.g., those with compromised immune systems, pregnant women, etc., for who other smallpox vaccines are (or will be) contraindicated (due to concerns about systemic vaccinia virus infection). MVA has previously been used in over 100,000 persons as a smallpox vaccine in Germany, so it has a record of relative safety and presumed efficacy. New MVA vaccines are in clinical trials. See the MVA entry (#541).
Sanofi Pasteur has initiated development and production in Europe of a new cell cultured smallpox vaccine. The company is also redirecting research programs towards the development of an improved smallpox vaccine based on proprietary highly attenuated vaccinia virus vectors, particularly the NYVAC vaccinia virus and other poxvirus vaccine vectors, from the company’s Virogenetics Corp. subsidiary.
Competition: VaxGen Inc. (S. San Francisco, CA) in collaboration with Chemo-Sero Research Institute (Kaketsuken; Japan), had been collaboratively developing LC16m8, an attenuated cell cultured vaccinia virus-based smallpox vaccine for the U.S. and international markets. LC16m8 is a cloned virus vaccine produced in cell culture that has been shown to be less neurovirulent than unattenuated strains of vaccinia vaccines in preclinical models. LC16m8 manufactured by Kaketsuken has been used in Japan in laboratory workers, medical and emergency response personnel. LC16m8 was initially developed by Kaket-suken in Japan to address the need for an attenuated smallpox vaccine that was as effective, but safer than conventional, unattenuated smallpox vaccines. Studies involving approximately 90,000 children were conducted in Japan, where LC16m8 is currently approved and manufactured commercially. With the withdrawal of VaxGen, all rights and clinical data related to the collaboration reverted to markets. Clinical studies indicate that LC16m8 produces a smaller pock at the site of vaccination (indicating less pathogenicity), but provides immunity comparable to that from prior vaccines, e.g., Dryvax. Phase I/II U.S. trials began in Oct. 2004, with volunteers receiving either LC16m8 or Dryvax. In June 2007, VaxGen withdrew from its LC16m8 collaboration with the Chemo-Sero Research Institute.
CytoGenix Inc. is developing SynDNA, a plasmid DNA-based smallpox vaccine.
AlphaVax, Inc. is developing a smallpox vaccine.
Russian scientists, likely sponsored by the government, are reportedly developing an oral smallpox vaccine, restarting work from prior biological warfare programs.
Transgene S.A. is developing an MVA vector-based vaccine, MVA-Muc1-IL2 (TG4010), and initiated Phase IIb trials in Dec. 2005.
Chesapeake PERL, Inc. (C-PERL; Savage, MD) is developing a smallpox vaccine based on a recombinant baculovirus vector expressed in whole caterpillar larvae
NanoBio Corp. is developing a nasal nanoemulsion vaccine for smallpox, using a mixture of soybean oil, alcohol, water and detergents emulsified into ultra-small particles smaller than 400 nanometers wide, or 1/200th the width of a human hair. These are combined with antigen(s).
See also the Vaccinia Immune Globulin entry for smallpox therapeutics.
Index Terms:
Full monograph
535 Smallpox Vaccine Products
Nomenclature:
smallpox vaccine [SY]
vaccinia virus, live [SY]
variola virus vaccine [SY]
biopharmaceutical products
live microorganisms (as active agent)
vaccines, live
vaccines, viral
vaccines, viral
BHK-21 (C-13)
EU999 R&D Halted/Product Abandoned
NA
US666 Biodefense stockpile
NA
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