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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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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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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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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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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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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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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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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.
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