smallpox vaccine smallpox vaccine the smallpox vaccine is the first vaccine to have been developed against a contagious disease. in 1796, british physician edward jenner demonstrated that an infection with the relatively mild cowpox virus conferred immunity against the deadly smallpox virus. cowpox served as a natural vaccine until the modern smallpox vaccine emerged in the 20th century. from 1958 to 1977, the world health organization (who) conducted a global vaccination campaign that eradicated smallpox, making it the only human disease to be eradicated. although routine smallpox vaccination is no longer performed on the general public, the vaccine is still being produced to guard against bioterrorism, biological warfare, and mpox. smallpox vaccinethe smallpox vaccine diluent in a syringe alongside a vial of dryvax dried smallpox vaccine and bifurcated needlevaccine descriptiontargetsmallpoxvaccine typelive virusclinical datatrade namesacam2000, imvanex, jynneos, othersahfs/drugs.commicromedex detailed consumer information / acam2000license data us dailymed: smallpox pregnancycategory au: d routes ofadministrationsubcutaneousatc codej07bx01 (who) legal statuslegal status au: s4 (prescription only) ca: rx-only, schedule d uk: pom (prescription only) us: ℞-only eu: rx-only in general: ℞ (prescription only) identifiersdrugbankdb15497unii4sv59689skkeggd05295 the term vaccine derives from the latin word for cow, reflecting the origins of smallpox vaccination. edward jenner referred to cowpox as variolae vaccinae (smallpox of the cow). the origins of the smallpox vaccine became murky over time, especially after louis pasteur developed laboratory techniques for creating vaccines in the 19th century. allan watt downie demonstrated in 1939 that the modern smallpox vaccine was serologically distinct from cowpox, and vaccinia was subsequently recognized as a separate viral species. whole-genome sequencing has revealed that vaccinia is most closely related to horsepox, and the cowpox strains found in great britain are the least closely related to vaccinia. types as the oldest vaccine, the smallpox vaccine has gone through several generations of medical technology. from 1796 to the 1880s, the vaccine was transmitted from one person to another through arm-to-arm vaccination. smallpox vaccine was successfully maintained in cattle starting in the 1840s, and calf lymph vaccine became the leading smallpox vaccine in the 1880s. first-generation vaccines grown on the skin of live animals were widely distributed in the 1950s–1970s to eradicate smallpox. second-generation vaccines were grown in chorioallantoic membrane or cell cultures for greater purity, and they were used in some areas during the smallpox eradication campaign. third-generation vaccines are based on attenuated strains of vaccinia and saw limited use prior to the eradication of smallpox. all three generations of vaccine are available in stockpiles. first and second-generation vaccines contain live unattenuated vaccinia virus and can cause serious side effects in a small percentage of recipients, including death in 1–10 people per million vaccinations. third-generation vaccines are much safer due to the milder side effects of the attenuated vaccinia strains. second and third-generation vaccines are still being produced, with manufacturing capacity being built up in the 2000s due to fears of bioterrorism and biological warfare. first-generation the first-generation vaccines are manufactured by growing live vaccinia virus in the skin of live animals. most first-generation vaccines are calf lymph vaccines that were grown on the skin of cows, but other animals were also used, including sheep. the development of freeze-dried vaccine in the 1950s made it possible to preserve vaccinia virus for long periods of time without refrigeration, leading to the availability of freeze-dried vaccines such as dryvax.: 115 the vaccine is administered by multiple puncture of the skin (scarification) with a bifurcated needle that holds vaccine solution in the fork. the skin should be cleaned with water rather than alcohol, as the alcohol could inactivate the vaccinia virus.: 292 if alcohol is used, it must be allowed to evaporate completely before the vaccine is administered.: 292 vaccination results in a skin lesion that fills with pus and eventually crusts over. this manifestation of localized vaccinia infection is known as a vaccine "take" and demonstrates immunity to smallpox. after 2–3 weeks, the scab will fall off and leave behind a vaccine scar. first generation vaccines consist of live, unattenuated vaccinia virus. one-third of first-time vaccinees develop side effects significant enough to miss school, work, or other activities, or have difficulty sleeping. 15–20% of children receiving the vaccine for the first time develop fevers of over 102 °f (39 °c). the vaccinia lesion can transmit the virus to other people. rare side effects include postvaccinal encephalitis and myopericarditis. many countries have stockpiled first generation smallpox vaccines. in a 2006 predictive analysis of casualties if there were a mass vaccination of the populations of germany and the netherlands, it was estimated that a total of 9.8 people in the netherlands and 46.2 people in germany would die from uncontrolled vaccinia infection after being vaccinated with the new york city board of health strain. more deaths were predicted for vaccines based other strains: lister (55.1 netherlands, 268.5 germany) and bern (303.5 netherlands, 1,381 germany). second-generation the second-generation vaccines consist of live vaccinia virus grown in the chorioallantoic membrane or cell culture. the second-generation vaccines are also administered through scarification with a bifurcated needle, and they carry the same side effects as the first-generation vaccinia strain that was cloned. however, the use of eggs or cell culture allows for vaccine production in a sterile environment, while first-generation vaccine contains skin bacteria from the animal that the vaccine was grown on. ernest william goodpasture, alice miles woodruff, and g. john buddingh grew vaccinia virus on the chorioallantoic membrane of chicken embryos in 1932. the texas department of health began producing egg-based vaccine in 1939 and started using it in vaccination campaigns in 1948.: 588 lederle laboratories began selling its avianized smallpox vaccine in the united states in 1959. egg-based vaccine was also used widely in brazil, new zealand, and sweden, and on a smaller scale in many other countries. concerns about temperature stability and avian sarcoma leukosis virus prevented it from being used more widely during the eradication campaign, although no increase in leukemia was seen in brazil and sweden despite the presence of aslv in the chickens.: 588 vaccinia was first grown in cell culture in 1931 by thomas milton rivers. the who funded work in the 1960s at the dutch national institute for public health and the environment (rvim) on growing the lister/elstree strain in rabbit kidney cells and tested it in 45,443 indonesian children in 1973, with comparable results to the same strain of calf lymph vaccine.: 588–589 two other cell culture vaccines were developed from the lister strain in the 2000s: elstree-bn (bavarian nordic) and vv lister cep (chicken embryo primary, sanofi pasteur). lister/elstree-rvim was stockpiled in the netherlands, and elstree-bn was sold to some european countries for stockpiles. however, sanofi dropped its own vaccine after it acquired acambis in 2008. acam2000 is a vaccine developed by acambis, which was acquired by sanofi pasteur in 2008, before selling the smallpox vaccine to emergent biosolutions in 2017. six strains of vaccinia were isolated from 3,000 doses of dryvax and found to exhibit significant variation in virulence. the strain with the most similar virulence to the overall dryvax mixture was selected and grown in mrc-5 cells to make the acam1000 vaccine. after a successful phase i trial of acam1000, the virus was passaged three times in vero cells to develop acam2000, which entered mass production at baxter. the united states ordered over 200 million doses of acam2000 in 1999–2001 for its stockpile, and production is ongoing to replace expired vaccine. third-generation the third-generation vaccines are based on attenuated vaccinia viruses that are much less virulent and carry lesser side effects. the attenuated viruses may be replicating or non-replicating. mva modified vaccinia ankara (mva, german: modifiziertes vakziniavirus ankara) is a replication-incompetent variant of vaccinia that was developed in west germany through serial passage. the original ankara strain of vaccinia was maintained at the vaccine institute in ankara, turkey on donkeys and cows. the ankara strain was taken to west germany in 1953, where herrlich and mayr grew it on chorioallantoic membrane at the university of munich. after 572 serial passages, the vaccinia virus had lost over 14% of its genome and could no longer replicate in human cells. mva was used in west germany in 1977–1980, but the eradication of smallpox ended the vaccination campaign after only 120,000 doses. mva stimulates the production of fewer antibodies than replicating vaccines. during the smallpox eradication campaign, mva was considered to be a pre-vaccine that would be administered before a replicating vaccine to reduce the side effects, or an alternative vaccine that could be safely given to people at high risk from a replicating vaccine.: 585 japan evaluated mva and rejected it due to its low immunogenicity, deciding to develop its own attenuated vaccine instead. in the 2000s, mva was tested in animal models at much higher dosages. when mva is given to monkeys at 40 times the dosage of dryvax, it stimulates a more rapid immune response while still causing lesser side effects. mva-bn mva-bn (also known as: imvanex in the european union; imvamune in canada; and jynneos) is a vaccine manufactured by bavarian nordic by growing mva in cell culture. unlike replicating vaccines, mva-bn is administered by injection via the subcutaneous route and does not result in a vaccine "take." a "take" or "major cutaneous reaction" is a pustular lesion or an area of definite induration or congestion surrounding a central lesion, which can be a scab or an ulcer. mva-bn can also be administered intradermally to increase the number of available doses. it is safer for immunocompromised patients and those who are at risk from a vaccinia infection. mva-bn has been approved in the european union, canada, and the united states. clinical trials have found that mva-bn is safer and just as immunogenic as acam2000. lc16m8 lc16m8 is a replicating attenuated strain of vaccinia that is manufactured by kaketsuken in japan. working at the chiba serum institute in japan, so hashizume passaged the lister strain 45 times in primary rabbit kidney cells, interrupting the process after passages 36, 42, and 45 to grow clones on chorioallantoic membrane and select for pock size. the resulting variant was designated lc16m8 (lister clone 16, medium pocks, clone 8). unlike the severely-damaged mva, lc16m8 contains every gene that is present in the ancestral vaccinia. however, a single-nucleotide deletion truncates membrane protein b5r from a residue length of 317 to 92. although the truncated protein decreases production of extracellular enveloped virus, animal models have shown that antibodies against other membrane proteins are sufficient for immunity. lc16m8 was approved in japan in 1975 after testing in over 50,000 children. vaccination with lc16m8 results in a vaccine "take," but safety is similar to mva. safety vaccinia is infectious, which improves its effectiveness, but causes serious complications for people with impaired immune systems (for example chemotherapy and aids patients) or history of eczema, and is not considered safe for pregnant women. a woman planning on conceiving should not receive smallpox immunization. vaccines that only contain attenuated vaccinia viruses (an attenuated virus is one in which the pathogenicity has been decreased through serial passage) have been proposed, but some researchers have questioned the possible effectiveness of such a vaccine. according to the us centers for disease control and prevention (cdc), "within 3 days of being exposed to the virus, the vaccine might protect you from getting the disease. if you still get the disease, you might get much less sick than an unvaccinated person would. within 4 to 7 days of being exposed to the virus, the vaccine likely gives you some protection from the disease. if you still get the disease, you might not get as sick as an unvaccinated person would." in may 2007, the vaccines and related biological products advisory committee (vrbpac) of the u.s. food and drug administration (fda) voted unanimously that a new live virus vaccine produced by acambis, acam2000, is both safe and effective for use in persons at high risk of exposure to smallpox virus. however, due to the high rate of serious adverse effects, the vaccine will only be made available to the cdc for the strategic national stockpile. stockpiles since smallpox has been eradicated, the public is not routinely vaccinated against the disease. the world health organization maintained a stockpile of 200 million doses in 1980, to guard against reemergence of the disease, but 99% of the stockpile