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7 Development of Vaccines W idespread vaccination was key to the success of the smallpox eradication program. Because smallpox no longer circulates as a natural pathogen, routine vaccination of the general population has been discontinued. In the event of an outbreak, however, vaccination still would be the most effective means of preventing an epidemic, and cur- rent U.S. guidelines call for vaccination of selected persons for preparedness purposes. WHO has a vaccine stockpile and recommends that national governments maintain stores of smallpox vaccine. The 1999 IOM committee identified the need to maintain stores of smallpox vaccine: Adequate stocks of smallpox vaccine would have to be maintained if research were to be conducted on variola virus or if maintenance of a smallpox vaccination program were required. Live variola virus would be necessary if certain approaches to the development of novel types of smallpox vaccine were to be pursued. The 1999 committee noted that, at the time, stocks of live vaccinia virus were deteriorating and would likely need to be replenished. However, the committee determined that live variola virus would not be required for the development of live vaccinia vaccines based on traditional vaccine strains but produced with modern tissue culture techniques, as safety and efficacy could be measured against the parental vaccine produced in animals. The committee concluded that research involving live variola virus would be required for the development of nonreplicating virus, live-attenuated virus, 

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 LIVE VARIOLA VIRUS and subunit vaccines. The committee noted that such testing would also require as yet undeveloped animal models. This chapter examines in turn the history and current status of small- pox vaccine development, the scientific pathway to development, salient regulatory requirements, and the need for live variola virus in this work. HISTORy OF SMALLPOX VACCINE DEVELOPMENT Early attempts at preventing smallpox arose from the observations that people who survived the disease had lifetime protection against new expo- sures and that those who were exposed to variola virus via the cutaneous route had milder disease. To prevent life-threatening smallpox, attempts were made to expose individuals to the virus from scabs, a process known as variolation. In 1796, Edward Jenner reported that milkmaids who had cowpox were immune to smallpox, as were children inoculated with mate- rial taken from cowpox lesions (see Figure 7-1). The practice of “vacci- nation” subsequently became widespread in Europe and North America during the nineteenth century. Early Vaccine Development While standards for smallpox vaccine composition and delivery were initially lacking, by the 1960s WHO had established guidelines mandating a specific concentration (1 × 108 plaque-forming units per milliliter) and a specific method (multiple puncture with a bifurcated needle) for smallpox vaccination. Delivery via the bifurcated needle involves dipping the needle in a suspension of vaccinia virus and repeatedly pricking the skin. The strain used in the vaccine varied by country, and certain strains were less reactogenic than others, but WHO’s Intensified Smallpox Eradication Pro- gramme most often used the Lister strain (Parrino and Graham, 2006). Posteradication Era When smallpox threatened as many as one in four individuals, the risk of adverse effects of vaccination was less than the risk of contracting the disease itself. In the posteradication era, however, concerns about vac- cine safety take precedence. The growing number of immunocompromised individuals globally has also changed the risk/benefit calculations for any future widespread use of traditional vaccinia vaccines (Artenstein and Grabenstein, 2008). Until recently, Dryvax®, made from the NYCBH vaccinia strain, was the only smallpox vaccine licensed in the United States. Its efficacy against variola was established before eradication. However, use of live vaccinia

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 DEVELOPMENT OF VACCINES FIgURE 7-1 Cowpox pustule on the arm of Sarah Nelmes, from An Inquiry into the Causes and Effects of the Variolae Vaccinae by Edward Jenner (1749–1823), engraved by Pearce, ca 1800 (colored engraving) by William Skelton (1763–1848), Bibliotheque de la Facult� de M�decine, Paris, France/Archives Charmet/The Bridgeman Art Library.

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0 LIVE VARIOLA VIRUS virus can result in adverse effects, such as generalized and progressive vaccinia, eczema vaccinatum (EV), and postvaccinial encephalitis (see the discussion of first-generation vaccines below). Based on historical data obtained from two large-scale population-based surveys conducted through 1968, the risk of severe adverse effects is estimated to be around 1 in 1,000 vaccines; the risk of life-threatening or fatal effects is much lower (IOM, 2005). U.S. Experience In the wake of the 2001 terrorist attacks in the United States and the deaths due to anthrax that occurred soon after, national security and public health officials began to debate the adoption of a smallpox vaccination program to prepare the country for an intentional release of variola virus (Fauci, 2002; Seiler et al., 2003). In December 2002, the U.S. Government announced the Smallpox Vaccination Program, which involved the imme- diate and mandatory vaccination with Dryvax of up to 500,000 military personnel and the voluntary vaccination of up to 500,000 front-line health care workers and other critical personnel; this was to be followed by the vaccination of up to 10 million first responders, with plans to make the vac- cine available to members of the general public (Wilson, 2005). By October 2003, however, the broader program had effectively ended (Wilson, 2005). Four factors led to this outcome: the lack of trained personnel and funds in state health departments charged with implementation (IOM, 2005), the lack of an injury compensation program (Seiler et al., 2003; Wilson, 2005), the emergence of reports of unanticipated cardiac events (Wilson, 2005), and waning concern about an intentional release of variola virus (Seiler et al., 2003; Chapman et al., 2008). At the request of CDC, the IOM produced a series of letter reports and a final summary on issues related to implementation of the vaccination program (IOM, 2003a–e, 2004). This experience provided important contemporary information on challenges in vaccination implementation absent endemic disease, as well as the safety and immunogenicity of smallpox vaccine. No deaths attributable to the vaccine occurred among the military per- sonnel (730,580) and civilians (39,566) given Dryvax during the Smallpox Vaccination Program (Poland et al., 2005; Chapman et al., 2008). Numbers of reports of anticipated adverse events were similar to or lower than those in the past (Strikas et al., 2008). One military and one civilian vaccinee developed encephalitis, while 50 military personnel developed generalized vaccinia (Lewis et al., 2006). There were 112 cases of inadvertent infec- tion, 78 in vaccinees (autoinoculation) and 52 in close contacts of vaccinees (Poland et al., 2005). Myocardial ischemia was the most notable of the unanticipated adverse events, occurring in 24 military and 10 civilian vac-

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 DEVELOPMENT OF VACCINES cinees (Swerdlow et al., 2008). Five vaccinees, all of whom had preexisting heart disease, experienced fatal myocardial infarctions (Poland et al., 2005; Neff et al., 2008; Swerdlow et al., 2008); this rate did not exceed that expected among unvaccinated people with similar medical histories (Neff et al., 2008). Myopericarditis was diagnosed in 107 cases (86 military, 21 civilian) (Casey et al., 2005; Poland et al., 2005; Morgan et al., 2008), a significant increase associated with vaccinia vaccination (Neff et al., 2008; Strikas et al., 2008). This experience suggests that Dryvax and related products should not be given to individuals with known heart disease in the absence of a smallpox outbreak. CDC’s adverse event reporting system remains in place as a means to further assess rare or unexpected complica- tions of vaccinia vaccination (Thomas et al., 2008). CURRENT STATUS OF SMALLPOX VACCINE DEVELOPMENT The development of smallpox vaccines has progressed in three major phases, and vaccines are classified as first-, second-, or third-generation (see Table 7-1). First generation Traditional or first-generation smallpox vaccines were used during the eradication program. These vaccines, made using vaccinia virus, are Jennerian vaccines, defined as live viral vaccines that are attenuated by virtue of their host range specificity. Vaccinia causes a small infection of the skin at the vaccination site, called a “take,” which is the only known cor- relate of vaccine efficacy. These traditional vaccines were manufactured by growing the vaccinia virus in live animals, such as cattle and sheep (Collier, 1955, 1980). Dryvax is the only first-generation smallpox vaccine licensed in the United States (Artenstein and Grabenstein, 2008), while the Lister/ Elstree vaccine is available in Europe. These are lyophilized preparations of live vaccinia virus prepared from calf lymph. The vaccines are made by inoculating animals with seed virus derived from the NYCBH (for Dryvax) or Elstree strain of vaccinia. Although not subjected to any modern systematic scientific evaluation using live variola virus, the traditional vaccines set a benchmark against which all other smallpox vaccines must be measured because their efficacy has been established in the human population during natural outbreaks of smallpox. While the efficacy profile of first-generation vaccines is not completely known, the experience during eradication indicates a high level of effectiveness and infrequent serious adverse effects (IOM, 2005). In those who are immunocompromised and those who suffer from certain exfoliative skin conditions, however, the vaccinia virus can cause progres-

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 LIVE VARIOLA VIRUS TABLE 7-1 Vaccines and Strains Used Platform Product Parent Strain Rationale for Use First generation Dryvax® (Wyeth) Lymph-derived NYCBH Historical experience in vaccinia the United States through the era of routine use Sanofi Pasteur smallpox NYCBH Produced in 1956–1957 vaccine (SPSV) and used in the U.S. program of that era; in frozen storage since Elstree-RIVM (master Lister Historical experience in seed stock held at the the Intensified Smallpox National Institute of Eradication Programme Public Health in The Netherlands [RIVM]) Second generation Replication- ACAM2000™ NYCBH Defined manufacturing competent tissue- (Acambis): cloned virus process; reduced cultured vaccinia grown in Vero cells theoretical risk of virus adventitious agents compared with lymph- derived vaccine; less neurovirulent in animal models Elstree-BN Lister Defined manufacturing (Bavarian-Nordic) process; reduced theoretical risk of adventitious agents compared with lymph- derived vaccine Third generation Replication- LC16m8 vaccine: derived Lister Experience in more than competent, from 53 serial passages 100,000 Japanese children highly attenuated in rabbit kidney cells; between 1973 and 1975; vaccinia virus temperature-sensitive, better safety profile than small-plaque phenotype traditional live vaccinia, due to mutation in the less neurovirulent in B5R gene animals but unproven clinical efficacy

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 DEVELOPMENT OF VACCINES TABLE 7-1 Continued Platform Product Parent Strain Rationale for Use Replication- MVA, derived from more Ankara Theoretically improved deficient, highly than 570 serial passages safety profile, especially for attenuated in chicken embryo those in whom live vaccinia virus fibroblasts: IMVAMUNE vaccinia is contraindicated; (Bavarian-Nordic); TBC- used in 120,000 primary MVA (Therion) vaccinees in Germany in 1970s but unproven clinical efficacy NYVAC (Sanofi-Pasteur): Copenhagen Theoretically improved attenuated by the safety profile, especially for deletion of 18 open those in whom live reading frames from a vaccinia is contraindicated plaque-cloned vaccinia isolate Subunit vaccines Recombinant proteins; Vaccinia Theoretically improved plasmid DNA viruses, safety profile different sources SOURCE: Adapted from Artenstein and Grabenstein, 2008. sive or necrotizing vaccinia and EV, respectively. Progressive vaccinia is generally fatal, while EV is life-threatening. Moreover, because the vaccine site contains infectious virus, vaccinia can be transmitted to close contacts, putting these people unintentionally at risk (Lane et al., 1969; Fenner et al., 1988). EV has long been one of the most serious adverse effects of vaccinia vaccination. It occurs in people with atopic dermatitis (AD), a condition associated with skin barrier dysfunction and defects in antiviral immunity (Wollenberg and Enger, 2004). The estimated incidence of EV in primary vaccinees is 40 in 1,000,000 (CDC). EV is characterized by extensive vac- cina growth at the inoculation site or at the area affected by eczema. A recent case of life-threatening EV occurred in a child with AD who became infected by household contact with his father, who had been vaccinated against smallpox (Vora et al., 2008) (see also Chapter 6). With the increased incidence of AD, the potential risk of EV and its dire consequences in primary vaccinees and their contacts with AD cannot be underestimated (Horii et al., 2007). The pathogenesis of EV is not completely understood, but important scientific advances have occurred since the 1999 IOM report was issued.

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 LIVE VARIOLA VIRUS Keratinocytes are the predominant cell type in the epidermis. Liu and col- leagues (2005) reported that vaccinia virus had limited replicative capacity in human keratinocytes and that infection induced keratinocytes to produce Th2 cytokines. Howell and colleagues (2004) showed that cathelicidin, an antimicrobial peptide produced by injured or infected skin, reduces vaccinia infectivity. Cathelicidin-deficient mice developed larger and more numer- ous skin lesions when infected by scarification with vaccinia virus. It was found that cathelicidin production rises in response to vaccinia infection of skin biopsies, and this response is attenuated in vaccinia-infected AD skin (Howell et al., 2006). Deng and colleagues (2008) reported that infection with a mutant vaccinia virus, ∆E3L (in which dsRNA-binding protein E3L is deleted) could be sensed by keratinocytes through an MAVS- and IRF3- dependent cytosolic RNA-sensing pathway to trigger the production of interferon and proinflammatory cytokines and chemokines. Further studies are needed to determine whether the skin of individuals with AD is deficient in mounting interferon responses to vaccinia infection. In the modern era, from the late nineteenth century through global eradication, the development of first-generation vaccines was driven by concerns about both safety, with the aim of minimizing the reactogenicity of vaccines, and efficacy, manifested by the take rate, which served as a readily quantifiable correlate of efficacy. Low take rates in vaccine lots were generally ascribed to problems with production. During the eradication campaign, WHO addressed these concerns by acting to improve production processes in member nations and setting minimum standards for vaccine concentration as assessed by pock formation on chorioallantoic membrane (CAM), the heat stability of vaccine lots, and provision of standardized seed lots from the WHO collaborating centers (Fenner et al., 1988, Chapter 11). Consequently, live variola virus itself was not central to the development of first-generation vaccines beyond the original observations of Jenner himself and his immediate followers. Second generation Because of the relatively high incidence of mild complications associ- ated with tradiational vaccinia vaccines and the risk of severe complica- tions in people with certain preexisting medical conditions, alternative vaccines are desirable. In addition, the use of live animals for production is inconsistent with modern pharmaceutical manufacturing practices and raises a theoretical concern about the spread of transmissible spongiform encephalopathies (TSEs), such as bovine spongiform encephalopathy (BSE)/ mad cow disease. The second-generation vaccines use live replicating vaccinia virus, but are produced using modern tissue culture techniques rather than growth

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 DEVELOPMENT OF VACCINES in live animals. In a notable achievement since the first IOM report was issued, a second-generation vaccine, ACAM2000™, was recently licensed for use against smallpox by the FDA and has been added to the U.S. Strategic National Stockpile. The second-generation and first-generation vaccines are similar, but the former are more acceptable under the modern regulatory framework and avoid the potential hazards associated with TSEs. The same strains used in first-generation vaccines can also be used in second-generation vaccines. For example, ACAM2000 uses the NYCBH strain of vaccinia, prepared in Vero cells (Frey et al., 2009). This means that vaccines derived from tissue culture should bear a strong similarity to first-generation vaccines in terms of efficacy, but therefore also have the potential to cause the same spectrum of complications in both healthy recipients and those with medical contraindications, as well as in contacts of recipients accidentally infected. In double-blind randomized trials assessing probable efficacy and safety, no significant differences in response (take rates and rates of adverse effects) were seen between ACAM2000 and Dryvax (Artenstein and Grabenstein, 2008; Frey et al., 2009). The clinical safety data on ACAM2000 suggest a continued risk of myopericarditis. The rate of myopericarditis in the Dryvax group is higher than that reported by the earlier U.S. Department of Defense (DOD) or CDC programs, but neither program had active sur- veillance in place for this particular adverse event (Greenberg and Kennedy, 2008). Another second-generation vaccine, CCSV, derived from cell culture, also showed a good safety profile in initial tests; however, there are no further plans to develop this vaccine (Bonilla-Guerrero and Poland, 2003; Artenstein and Grabenstein, 2008). ACAM2000 is licensed only for use in the Strategic National Stockpile. Live variola virus was not required for licensure of the second-generation ACAM2000 vaccine. VECTOR reports production of a recombinant and highly attenuated strain of vaccinia virus, b7, 5S2-S, by the insertion of a hepatitis B (HB) DNA fragment into the thymidine kinase gene of vaccinia virus strain, L-IVP, coding for synthesis of the HBs and preS2-S proteins (Russian Federation Patent #1575576). Currently, based on this strain, a second- generation bivalent egg-based smallpox vaccine for oral administration is being developed (Russian Federation Patent #2076735). Increased safety of such a vaccine for the organism as compared with cutaneous smallpox vaccination arises from the switching off of the thymidine kinase gene of vaccinia virus that results from inserting the DNA fragment of HB virus. This vaccine has reportedly passed preclinical studies and Phase I clinical trials in a group of 100 subjects (Sergeev et al., 2004; Pliasunov et al., 2006; personal communication, Ilya Drozdov, WHOCC for Orthopoxvirus Diagnosis and Repository for Variola Virus Strains and DNA, March 27, 2009).

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 LIVE VARIOLA VIRUS In addition, VECTOR is developing highly attenuated variants of live vaccines based on vaccinia virus using direct deletion of several genes, as well as DNA vaccines against smallpox. Such developments are in the preclinical phase (Maksyutov et al., 2006; personal communication, Ilya Drozdov, WHOCC for Orthopoxvirus Diagnosis and Repository for Variola Virus Strains and DNA, March 27, 2009). Third generation The development of safer smallpox vaccines is necessary because of the adverse events associated with first-generation vaccines; as noted, second- generation vaccines resemble first-generation vaccines in that they contain infectious vaccina. In light of those adverse events, it has been estimated that at least 25 percent of the U.S. population should not receive traditional smallpox vaccines in the absence of an outbreak (Kemper et al., 2002). Smallpox vaccines that have an improved or potentially improved safety profile with respect to complications are often referred to as third- or next- generation smallpox vaccines, and can be subdivided into three distinct groups: nonreplicating virus, live-attenuated virus, and subunit vaccines. Candidate nonreplicating virus vaccines include vaccinia virus derivates such as MVA (modified Vaccinia Ankara) and Nyvac (Hochstein-Mintzel et al., 1975; Tartaglia et al., 1992; Mahnel and Mayr, 1994; Paoletti et al., 1994). These are viruses that replicate in tissue culture but cannot replicate effectively in a human host or in immunocompromised animals. This vastly improves their safety profile, although there are probable increased pro- duction costs relative to the second-generation vaccines. While the leading candidate, MVA, was previously used widely in humans in the former West Germany in the 1970s (Mayr et al., 1978), variola virus was not endemic in West Germany at that time, and therefore no clinical data exist on MVA’s effectiveness against smallpox. MVA has a good safety profile and has been evaluated extensively as a third-generation smallpox vaccine. It was originally derived from vaccinia strain Ankara by more than 570 serial passages of the virus in primary chicken embryo fibroblasts (CEFs). MVA is highly attenuated and can- not replicate in humans and most mammalian cells. It has a 31 kilobase pair deletion from its parental genome and lacks several of the immuno- modulatory gene products, such as soluble receptors for IFN-α, β, and γ; tumor necrosis factor; and CC chemokines. It also lacks proteins that affect host range and NF-κB signaling, such as K1L and A52R (Meyer et al., 1991; Antonie et al., 1998; Blanchard et al., 1998). MVA infection of human monocyte-derived dendritic cells (DCs) increases the surface expression of costimulatory molecules and has a mod- erate induction of proinflammatory cytokines, whereas wild-type vaccinia

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 DEVELOPMENT OF VACCINES strains do not (Drillien et al., 2004). Waibler and colleagues (2007) reported that MVA induces IFN-α in murine plasmacytoid DCs via a largely toll-like receptor (TLR)-independent mechanism. Samuelsson and colleagues (2008) demonstrated that MVA induces IFN-α in murine conventional DCs and plasmacytoid DCs via both TLR9-dependent and independent mechanisms. In a murine model, vaccination with MVA intranasally at the same time as or 2 days after a lethal dose of ectromelia virus (ECTV) protected the animals from death. MVA-mediated protection is partially dependent on the type I interferon receptor. These results provide some basis for the immunogenicity of MVA as a vaccine and suggest that it might be useful against a lethal poxvirus infection in a postexposure setting. Mice with severe combined immunodeficiency can tolerate a 1,000 times higher dose of MVA than the standard vaccine strain (Dryvax) (Wyatt et al., 2004). Mice developed virus-specific CD8+ T cells and neutralizing antibodies after MVA inoculation, and vaccinated mice were protected against lethal intranasal challenge of vaccinia WR strain. Mice deficient in B cells or CD8+ T cells were also protected, whereas CD4 or MHC Class II knockout mice were poorly protected (Wyatt et al., 2004). Extensive studies conduced in nonhuman primate models have dem- onstrated the efficacy of MVA against lethal monkeypox infection. MVA is safe in immune-deficient nonhuman primates (Stittelaar et al., 2001). Immunization with two doses of MVA alone or one dose of MVA followed by Dryvax generated neutralizing antibodies and antiviral-specific T cell responses equivalent to or higher than those induced by Dryvax alone and provided protection against an intravenous lethal challenge with monkey- pox in a nonhuman primate model (Earl et al., 2004). Protection against respiratory challenges with monkeypox virus via the intratracheal route has also been shown with MVA (Stittelaar et al., 2005). MVA leads to a more rapid immune response than Dryvax in nonhuman primates. MVA admin- istration 4 days prior to intravenous challenge with monkeypox provided protection, whereas Dryvax did not (Earl et al., 2008). The results of the above studies suggest that MVA is safe and may be effective against smallpox (Mahnel, 1985; McCurdy et al., 2004; Coulibaly et al., 2005; Meseda et al., 2005; Slifka, 2005; Belyakov et al., 2006; Phelps et al., 2007; Damon et al., 2009). MVA vaccines are currently under devel- opment (Vollmar et al., 2006; Parrino et al., 2007). Live-attenuated virus vaccines that retain limited ability to replicate in human hosts offer another route to a safer smallpox vaccine that may be appropriate for use in those for whom second-generation vaccines pose too high a risk. These vaccines, such as LC16m8, are more similar than nonreplicating virus vaccines to the second-generation vaccines by virtue of their ability to replicate in the vaccinee, but reduce the risk of compli- cations. The LC16m8 strain is derived from the Lister/Elstree traditional

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00 LIVE VARIOLA VIRUS including those that cause high levels of mortality with different pathologi- cal profiles (e.g., monkeypox in macaques, ectromelia in mice, vaccinia in mice), allows them to be to be combined in this type of approach to support the expectation that a vaccine that protects against mortality in all of these models will at the very least modify the course of disease in smallpox and increase the probability of survival. The ability of the nonreplicating and live-attenuated virus vaccines to induce de novo production of virus proteins within host cells is an impor- tant feature shared with first- and second-generation vaccines. Neverthe- less, the alterations that confer the dramatically improved safety profiles of these third-generation vaccines may plausibly have both direct and indirect effects on efficacy. The inability of protein-based subunit vaccines to direct de novo protein synthesis in the vaccinee constitutes a major departure from the first- and second-generation vaccines. Consequently, notwithstanding the efficacy of a number of third-generation vaccine approaches in animal models using nonvariola orthopoxviruses, a degree of doubt remains with regard to their potential efficacy against variola virus. The ability to dissect the immune response induced by a vaccine does facilitate the establishment of immune correlates of protection, as has been done with, for example, vaccines against HB virus, and this can generate the necessary confidence that a vaccine is effective at either a population or individual level (Roome et al., 1993). However, concerns remain when immune profiles cannot be directly correlated with efficacy by means of prospective human trials involving the disease agent for which the vaccine is developed. For an eradicated disease, such a trial could utilize the disease agent in an animal model. However, the disconcertingly accelerated dis- ease course and extremely high challenge dose that characterize the extant lethal variola model in nonhuman primates mean this model is inadequate for the purpose of rejecting a vaccine candidate. The model as it currently stands is thus of questionable value for the development and licensure of a third-generation vaccine. REgULATORy REqUIREMENTS In contrast to the challenges affecting the regulatory approval of anti- viral agents for smallpox (see Chapter 6), the pathway for licensure of new vaccines is more straightforward. Although, in contrast to antivirals, the FDA has not issued formal guidance pertaining to the development and licensure of new smallpox vaccines, potentially acceptable regulatory path- ways have been suggested in several publically available documents and presentations to which FDA officials have contributed. The most pertinent event that occurred following issuance of the 1999 IOM report was the licensure of the second-generation vaccine

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0 DEVELOPMENT OF VACCINES ACAM2000 in 2007. Approval of ACAM2000 was based primarily on clinical noninferiority in comparison with the first-generation vaccine Dryvax, with take rates, plaque reduction neutralization (PRNT) anti- body responses, and acute safety parameters found to be similar in the two study groups. The development of endpoints that could lead to the approval of third- generation vaccines has proven to be more challenging, as the accepted marker of clinical efficacy—a take—is not elicited. Under these circum- stances, the Animal Rule (see Chapter 1) would play an important role in assessing efficacy, ideally in comparison with a first-generation vaccine. The FDA has also indicated that for a postevent scenario, efficacy will need to be established in at least two orthopoxvirus challenge animal models (Merchlinsky, 2008) using a dosing regimen appropriate for a postevent setting, which will most likely consist of a single dose. Moreover, because a postevent setting may also include individuals who have actually been exposed to smallpox, the time required for the induction of a protective response for a third-generation vaccine will be an important consideration in the design of animal and human studies. Finally, the use of a respiratory challenge model (preferably a nonhuman primate) should be considered, since this would be the most likely route of human exposure. Although a path to licensure can be envisaged, the concerns raised in the previous section suggest that replacement of first- and second-generation vaccines with third-generation vaccines that do not produce lesions at the site of inoculation may be inadvisable for those segments of the population that have no contraindications for a traditional smallpox vaccine. There are nevertheless clear concerns for those segments of the population that have such contraindications. The path to licensure described above may be appropriate for less reactogenic third-generation vaccines developed specifi - cally for these individuals, providing tangible benefits associated with, at minimum, modification of the course of disease and increased probability of survival. For the protection of populations and individuals with contraindications, the challenge is not simply to protect against smallpox, but also to protect against adverse events associated with first- and second-generation vac- cines, including contact transmission of vaccinia. It appears unlikely that a third-generation vaccine incapable of protecting these individuals against progressive vaccinia, severe generalized vaccinia, or EV would have utility against smallpox in such cases. Thus there is considerable scientific merit in focusing the development of third-generation vaccines on the prevention of adverse events associated with first- and second-generation vaccines rather than on the prevention of smallpox.

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0 LIVE VARIOLA VIRUS NEED FOR LIVE VARIOLA VIRUS Although no modern prospective clinical trial of first-generation small- pox vaccines has examined protection from smallpox, experiments were conducted in the late eighteenth and early nineteenth centuries in which people were vaccinated and subsequently challenged by variolation with material taken from a smallpox patient, in an approach that would clearly be unacceptable by modern standards. The first of these were the original experiments of Edward Jenner, in which a child, James Phipps, was inocu- lated with cowpox by Jenner and subsequently challenged by variolation; Jenner undertook variolation challenges on two additional vaccinated chil- dren. In 1800, an American physician, Benjamin Waterhouse of Harvard University, vaccinated his son and six members of his household and subse- quently arranged to have them challenged by variolation. In 1803, 17,000 vaccinations were performed in Germany; more than 8,000 of the vaccinees were subsequently challenged by variolation (Dixon, 1962). The ability to test the efficacy of vaccination by variolation challenges would necessarily have been lost in many communities as the incidence of smallpox, and thus the supply of variolation material, declined. The true efficacy of the first-generation vaccines was established through the experience of physi- cians and vaccinators and the success of the global eradication campaign, but there is little or no surviving evidence of evaluation in what could be considered a controlled clinical trial. Perhaps one of the most striking advances resulting from recent work on replacement smallpox vaccines is the number of animal models that have been developed and are ready for use to examine efficacy (see Chapter 4). The basis for the success of the traditional vaccinia-based vaccine is its very close relatedness to variola. Similar levels of relatedness are apparent among all old-world orthopoxviruses, and this means they all induce a degree of protective immunity to the other members of the genus. Thus, vaccinia is able to induce immunity to smallpox and monkeypox in man, to monkey- pox in monkeys, to mousepox (ectromelia) in mice, and to rabbitpox in rabbits, to name but a few. This has allowed new candidate vaccines to be extensively benchmarked against the first-generation vaccines even though no animal model using variola itself is suitable for vaccine studies. The current status of animal models, most of which are suitable for development to Good Laboratory Practices (GLP) standards, combined with the existence of an acceptable surrogate for clinical efficacy in humans (i.e., take rates), obviates the need to use live variola virus to achieve licensure of second-generation vaccines or third-generation live-attenuated vaccines that can replicate intradermally and produce a lesion at the site of inoculation. Although the FDA has thus far indicated that licensure of nonreplicating vaccinia-based vaccines (e.g., MVA) or other third-generation vaccines for

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0 DEVELOPMENT OF VACCINES use in the general population will not necessarily require animal challenge models using live variola virus, such models, along with evidence of appro- priate humoral and cellular immune responses against live variola virus in humans, would provide far more convincing evidence of efficacy. However, the development and use of such vaccines under Emergency Use Authoriza- tion (EUA) (see Chapter 1) may be justified on the basis of less stringent evidence of efficacy and may not require the use of live variola virus. For example, challenge studies based on monkeypox in nonhuman primates or other surrogate viruses, as well as neutralizing antibody and cellular immune responses in humans that are shown to be comparable to those elicited by first- or second-generation vaccines, could provide sufficient confidence for these vaccines to be used to prevent smallpox. In addition, evidence of the clinical efficacy of such a vaccine against human monkeypox disease would support such use. While the charge to this committee was to consider variola virus, one cannot overlook the fact that the orthopoxvirus of greatest current public health concern is monkeypox. Monkeypox is endemic in central Africa and causes a severe, acute human disease that is very similar to smallpox and results in significant mortality (Hutin et al., 2001; Lederman et al., 2007; Rimoin et al., 2007). Although third-generation vaccines remain of interest for the control of potential smallpox outbreaks, their development may be more appropriately directed at the control of human monkeypox in areas where a significant proportion of the population may have medical contra- indications for first- and second-generation vaccines, but are at significant risk of monkeypox virus infection. REFERENCES Antonie, G., F. Scheiflinger, F. Dorner, and F. G. Falkner. 1998. The complete genomic sequence of the modified vaccinia Ankara strain: comparison with other orthopoxviruses. Virology 244:365–396. Artenstein, A. W., and J. D. Grabenstein. 2008. Smallpox vaccines for biodefense: Need and feasibility. Expert Review of Vaccines 7(8):1225–1237. Belyakov, I. M., P. Earl, A. Dzutsev, V. A. Kuznetsov, M. Lemon, L. S. Wyatt, J. T. Snyder, J. D. Ahlers, G. Franchini, B. Moss, and J. A. Berzofsky. 2003. Shared modes of protec- tion against poxvirus infection by attenuated and conventional smallpox vaccine viruses. Proceedings of the National Academy of Sciences of the United States of America 100:9458–9463. Belyakov, I. M., D. Isakov, Q. Zhu, A. Dzutsev, D. Klinman, and J. A. Berzofsky. 2006. Enhancement of CD8+ T cell immunity in the lung by CpG oligodeoxynucleotides increases protective efficacy of a modified vaccinia Ankara vaccine against lethal poxvirus infection even in a CD4-deficient host. Journal of Immunology 177:6336–6343. Blanchard, T. J., A. Alcami, P. Andrea, and G. L. Smith. 1998. Modified vaccinia virus Ankara undergoes limited replication in human cells and lacks several immunomodulatory proteins: Implications for use as a human vaccine. Journal of General Virology 79:1159–1167.

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