Clinical Infectious Diseases Advance Access published June 23, 2014
1
A Shigella vaccine against prevalent serotypes Lillian L. Van De Verg1, Malabi M. Venkatesan2
cr ipt
1Shigella Scientific Officer, Enteric Vaccine Initiative, Vaccine Development Global
Program, PATH, 455 Massachusetts Ave. NW, Washington, DC 20001‐2621 2 Chief, Live Shigella Vaccines, Bacterial Diseases Branch, Walter Reed Army Institute of Research, 503, Robert Grant Avenue, Silver Spring, MD. 20910 Corresponding Author: DIRECT 202 540 4459, FAX 202 457 1466, [email protected] Alternate Corresponding Author: Tel#: 301-319-9764, Fax#: 301-319-9801, Email:
us an M pt ed ce Ac © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: [email protected].
Downloaded from http://cid.oxfordjournals.org/ at University of Waikato Library on July 10, 2014
[email protected]
2 A Shigella vaccine against prevalent serotypes
cr ipt
Dysentery due to Shigella is a severe, intensely inflammatory infection that
disproportionately affects the very young in less developed parts of the world where there is little to no access to clean water or sanitation. Mortality due to shigellosis has
decreased significantly in the last two to three decades, arguably due in large part to the
us
diarrheal disease due to other shigellae has remained high. Worldwide, Shigella is
an
estimated to cause 80–120 million episodes of diarrhea and >100,000 deaths annually,
M
mostly in children less than 5 years of age (1).
The recently published Global Enteric Multicenter Study (GEMS) is a large-scale survey of the incidence and causative agents of moderate-to-severe diarrheal disease in young
pt ed
children 0-59 months of age residing in low income parts of seven countries in Africa and South Asia (2). In children 0-11 months of age, rotavirus and enterotoxigenic E. coli (ETEC) were often the leading agents of moderate-to-severe diarrhea. In the older children ages 12-59 months, Shigella became the lead agent overall. Children subjected
ce
to repeated bouts of diarrheal diseases such as shigellosis are susceptible to faltering in physical growth and cognitive development. A vaccine against Shigella may be viewed
Ac
by parents and public health authorities as a welcome means to counteract the multiple short- and long-term effects of infection. Travelers and members of the military are also vulnerable to infection, and a vaccine may be beneficial to these groups as well.
Downloaded from http://cid.oxfordjournals.org/ at University of Waikato Library on July 10, 2014
virtual disappearance of major epidemics of S. dysenteriae 1. However, the incidence of
3 A compelling case can be made for development of a pediatric Shigella vaccine, but there has been less clarity on optimizing coverage in light of the high degree of diversity
LPS) that is exposed on the bacterial surface.
cr ipt
observed in the protective antigen—the O-polysaccharide (O-antigen that is part of the
Serological classification of the S. flexneri
serotypes is based on the use of rabbit antisera obtained by immunization with heat-killed bacteria and made specific by absorption with S. flexneri strains related to the
us
3 group antigens (3,4; 6; 7,8) have been identified (4). Combinations of type and group
an
antigens can be found in individual S. flexneri strains with the type and group antigens shared among the S. flexneri serotypes and subserotypes. Comparative analyses have
M
identified the epitopes of most of the type and group antigens (5,6). Primate studies (7) and human clinical trials (8) have suggested that protection against Shigella infections is O-antigen dependent. The challenge is that there are more than 50 serotypes and
pt ed
subserotypes of Shigella including at least 14 serotypes of S. flexneri, 20 serotypes of S. boydii, 15 serotypes of S. dysenteriae and one serotype of S. sonnei.
To close the knowledge gap regarding the distribution of endemic serotypes that most
ce
affect children under 5, Livio et al. serotyped 1130 isolates recovered from the GEMS study. They showed that S. sonnei and S. flexneri serotype 2a were the predominant
Ac
shigellae, with the remaining S. flexneri serotypes occurring at much lower frequencies. Remarkably S. sonnei and S. flexneri 2a were also the predominant serotypes identified in a large scale study conducted by von Seidlein et al. among nearly 3000 cases of shigellosis in subjects ages 70 years of age residing in 6 countries in East,
Downloaded from http://cid.oxfordjournals.org/ at University of Waikato Library on July 10, 2014
immunizing strain (3). Using such methods to date seven type antigens (type 1-VIII) and
4 Southeast and South Asia (9). In both studies, S. dysenteriae and S. boydii were infrequently isolated (generally ca 5% overall). There is less information on South
cr ipt
America, where endemic Shigella disease may also be found but where large scale
epidemiological data are not available. However, available reports do indicate that S. sonnei and S. flexneri 2a are predominant there as well (10). Indeed the earliest live attenuated Shigella vaccines tested in the field over 40 years ago by Mel included
us
by chronological and geographical distances, there has been a consistent observation that
an
an effective Shigella vaccine should include at a minimum S. sonnei and S. flexneri 2a to provide coverage of approximately 40-50% of endemic disease. The question arises if
as individual components.
M
this coverage can be improved without having to include all the other flexneri serotypes
pt ed
The paper by Livio et al. extends observations from the GEMS study to postulate that a combination of 4 components, S. flexneri serotypes 2a, 3a and S. flexneri 6 as well as S. sonnei can provide an overall coverage of 88% through homologous protection and cross protection among the S. flexneri serotypes based on shared type and group O-antigen
ce
determinants. This principle has been tested in several animal model-based studies, with the most recent being reported by Noriega et al. (11). In that study, cross-protection by a
Ac
bivalent S. flexneri 2a/S. flexneri 3a vaccine in the guinea pig Sereny challenge model varied from 20% to 92%, with the strongest efficacy seen when the challenge strain shared both group and type antigens with the vaccine strains. Nonetheless the study did
Downloaded from http://cid.oxfordjournals.org/ at University of Waikato Library on July 10, 2014
S. sonnei and S. flexneri 2a in the formulation (8). Hence, based on data widely separated
5 show that cross-protection may be achieved through vaccination with strains that express
cr ipt
shared O-antigen epitopes.
The Livio study provides up-to-date data to inform a more broadly effective Shigella vaccine, particularly for children in the developing world. The ultimate test will be
achieved through studies in humans. There are clinical challenge models for S. sonnei
us
field studies will rely on this endemicity as well. Demonstrating efficacy of a
an
quadrivalent Shigella vaccines against the lesser endemic strains will be a bigger challenge. It would not be practical or desirable to develop human challenge models for
M
all the known S. flexneri serotypes hence in vitro and/or in vivo assays may be the only realistic alternative. Animal models that have been used include rabbits, mice, guinea pigs and non-human primates. While all of these have limitations they are likely useful
pt ed
for early evaluations of vaccine candidates. Evaluating potential efficacy of Shigella vaccines using post immunization samples from humans has relied in large part on traditional methods such as ELISA or ELISPOT to measure O-antigen specific mucosal and systemic antibodies, although a correlate of protection has not been established. A
ce
different approach could be the use of functional antibody assays (12) to evaluate
Ac
efficacy.
Several live attenuated, inactivated whole cell and subunit vaccine candidates based on serotype protection are either in clinical trials or soon to undergo clinical evaluations. These trials offer timely opportunities to evaluate the potential for a much needed,
Downloaded from http://cid.oxfordjournals.org/ at University of Waikato Library on July 10, 2014
and S. flexneri 2a to test vaccine efficacy against these predominant endemic strains, and
6 broadly protective multivalent Shigella vaccine. The Livio study provides useful data for
The authors have no reported conflicts of interest.
REFERENCES
us
1. Diarrhoeal Diseases (Updated February 2009) page. World Health Organization website. Available at: http://www.who.int/vaccine_research/diseases/diarrhoeal/en/index.html.
an
2. Kotloff KL, Nataro JP, Blackwelder WC et al. Burden and aetiology of diarrhoeal disease in infants and young children in developing countries (the Global Enteric Multicenter Study, GEMS): a prospective, case-control study. Lancet 2013; Jul 20;382(9888):209-22
M
3. Carlin NI, Wehler T, Lindberg AA. Shigella flexneri O-antigen epitopes: chemical and immunochemical analyses reveal that epitopes of type III and group 6 antigens are identical. Infect Immun. 1986; Jul;53(1):110-5.
5.
pt ed
4. Liu B, Knirel YA, Feng L et al. Structure and genetics of Shigella O antigens. FEMS Microb. Review 2008; 32:627-653. Kenne L, Lindberg B, Petersson K et al. Structural studies of Shigella flexneri Oantigens. Eur J Biochem. 1978; 91(1):279-84.
6. Perepelov AV, Shekht ME, Liu B et al. Shigella flexneri O-antigens revisited: final elucidation of the O-acetylation profiles and a survey of the O-antigen structure diversity. FEMS Immunol Med Microbiol. 2012; 66(2):201-10
ce
7. Formal SB, Oaks EV, Olsen RE et al. Effect of prior infection with virulent Shigella flexneri 2a on the resistance of monkeys to subsequent infection with Shigella sonnei. J Infect Dis. 1991; 164(3):533-7
Ac
8. Mel D, Gangarosa EJ, Radovanovic ML et al. Studies on vaccination against bacillary dysentery. 6. Protection of children by oral immunization with streptomycin-dependent Shigella strains. Bull World Health Organ. 1971;45(4):457-64. 9.
von Seidlein L, Kim DR, Ali M et al. A multicentre study of Shigella diarrhoea in six Asian countries: disease burden, clinical manifestations, and microbiology. PLoS Med. 2006; 3(9):e353.
Downloaded from http://cid.oxfordjournals.org/ at University of Waikato Library on July 10, 2014
cr ipt
addressing the serotypic requirements for such an effective vaccine.
7 10. Toro CS, Farfán M, Contreras I et al. Genetic analysis of antibiotic-resistance determinants in multidrug-resistant Shigella strains isolated from Chilean children. Epidemiol Infect. 2005;133(1):81-6
cr ipt
11. Noriega FR, Liao FM, Maneval DR et al. Strategy for cross-protection among Shigella flexneri serotypes. Infect Immun. 1999;67(2):782-8.
an M pt ed ce Ac
Downloaded from http://cid.oxfordjournals.org/ at University of Waikato Library on July 10, 2014
us
12. Burton RL, Nahm MH. Development and validation of a fourfold multiplexed opsonization assay (MOPA4) for pneumococcal antibodies. Clin Vaccine Immunol. 2006;13(9):1004-9.
1
A Shigella vaccine against prevalent serotypes Lillian L. Van De Verg1, Malabi M. Venkatesan2
cr ipt
1Shigella Scientific Officer, Enteric Vaccine Initiative, Vaccine Development Global
Program, PATH, 455 Massachusetts Ave. NW, Washington, DC 20001‐2621 2 Chief, Live Shigella Vaccines, Bacterial Diseases Branch, Walter Reed Army Institute of Research, 503, Robert Grant Avenue, Silver Spring, MD. 20910 Corresponding Author: DIRECT 202 540 4459, FAX 202 457 1466, [email protected] Alternate Corresponding Author: Tel#: 301-319-9764, Fax#: 301-319-9801, Email:
us an M pt ed ce Ac © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: [email protected].
Downloaded from http://cid.oxfordjournals.org/ at University of Waikato Library on July 10, 2014
[email protected]
2 A Shigella vaccine against prevalent serotypes
cr ipt
Dysentery due to Shigella is a severe, intensely inflammatory infection that
disproportionately affects the very young in less developed parts of the world where there is little to no access to clean water or sanitation. Mortality due to shigellosis has
decreased significantly in the last two to three decades, arguably due in large part to the
us
diarrheal disease due to other shigellae has remained high. Worldwide, Shigella is
an
estimated to cause 80–120 million episodes of diarrhea and >100,000 deaths annually,
M
mostly in children less than 5 years of age (1).
The recently published Global Enteric Multicenter Study (GEMS) is a large-scale survey of the incidence and causative agents of moderate-to-severe diarrheal disease in young
pt ed
children 0-59 months of age residing in low income parts of seven countries in Africa and South Asia (2). In children 0-11 months of age, rotavirus and enterotoxigenic E. coli (ETEC) were often the leading agents of moderate-to-severe diarrhea. In the older children ages 12-59 months, Shigella became the lead agent overall. Children subjected
ce
to repeated bouts of diarrheal diseases such as shigellosis are susceptible to faltering in physical growth and cognitive development. A vaccine against Shigella may be viewed
Ac
by parents and public health authorities as a welcome means to counteract the multiple short- and long-term effects of infection. Travelers and members of the military are also vulnerable to infection, and a vaccine may be beneficial to these groups as well.
Downloaded from http://cid.oxfordjournals.org/ at University of Waikato Library on July 10, 2014
virtual disappearance of major epidemics of S. dysenteriae 1. However, the incidence of
3 A compelling case can be made for development of a pediatric Shigella vaccine, but there has been less clarity on optimizing coverage in light of the high degree of diversity
LPS) that is exposed on the bacterial surface.
cr ipt
observed in the protective antigen—the O-polysaccharide (O-antigen that is part of the
Serological classification of the S. flexneri
serotypes is based on the use of rabbit antisera obtained by immunization with heat-killed bacteria and made specific by absorption with S. flexneri strains related to the
us
3 group antigens (3,4; 6; 7,8) have been identified (4). Combinations of type and group
an
antigens can be found in individual S. flexneri strains with the type and group antigens shared among the S. flexneri serotypes and subserotypes. Comparative analyses have
M
identified the epitopes of most of the type and group antigens (5,6). Primate studies (7) and human clinical trials (8) have suggested that protection against Shigella infections is O-antigen dependent. The challenge is that there are more than 50 serotypes and
pt ed
subserotypes of Shigella including at least 14 serotypes of S. flexneri, 20 serotypes of S. boydii, 15 serotypes of S. dysenteriae and one serotype of S. sonnei.
To close the knowledge gap regarding the distribution of endemic serotypes that most
ce
affect children under 5, Livio et al. serotyped 1130 isolates recovered from the GEMS study. They showed that S. sonnei and S. flexneri serotype 2a were the predominant
Ac
shigellae, with the remaining S. flexneri serotypes occurring at much lower frequencies. Remarkably S. sonnei and S. flexneri 2a were also the predominant serotypes identified in a large scale study conducted by von Seidlein et al. among nearly 3000 cases of shigellosis in subjects ages 70 years of age residing in 6 countries in East,
Downloaded from http://cid.oxfordjournals.org/ at University of Waikato Library on July 10, 2014
immunizing strain (3). Using such methods to date seven type antigens (type 1-VIII) and
4 Southeast and South Asia (9). In both studies, S. dysenteriae and S. boydii were infrequently isolated (generally ca 5% overall). There is less information on South
cr ipt
America, where endemic Shigella disease may also be found but where large scale
epidemiological data are not available. However, available reports do indicate that S. sonnei and S. flexneri 2a are predominant there as well (10). Indeed the earliest live attenuated Shigella vaccines tested in the field over 40 years ago by Mel included
us
by chronological and geographical distances, there has been a consistent observation that
an
an effective Shigella vaccine should include at a minimum S. sonnei and S. flexneri 2a to provide coverage of approximately 40-50% of endemic disease. The question arises if
as individual components.
M
this coverage can be improved without having to include all the other flexneri serotypes
pt ed
The paper by Livio et al. extends observations from the GEMS study to postulate that a combination of 4 components, S. flexneri serotypes 2a, 3a and S. flexneri 6 as well as S. sonnei can provide an overall coverage of 88% through homologous protection and cross protection among the S. flexneri serotypes based on shared type and group O-antigen
ce
determinants. This principle has been tested in several animal model-based studies, with the most recent being reported by Noriega et al. (11). In that study, cross-protection by a
Ac
bivalent S. flexneri 2a/S. flexneri 3a vaccine in the guinea pig Sereny challenge model varied from 20% to 92%, with the strongest efficacy seen when the challenge strain shared both group and type antigens with the vaccine strains. Nonetheless the study did
Downloaded from http://cid.oxfordjournals.org/ at University of Waikato Library on July 10, 2014
S. sonnei and S. flexneri 2a in the formulation (8). Hence, based on data widely separated
5 show that cross-protection may be achieved through vaccination with strains that express
cr ipt
shared O-antigen epitopes.
The Livio study provides up-to-date data to inform a more broadly effective Shigella vaccine, particularly for children in the developing world. The ultimate test will be
achieved through studies in humans. There are clinical challenge models for S. sonnei
us
field studies will rely on this endemicity as well. Demonstrating efficacy of a
an
quadrivalent Shigella vaccines against the lesser endemic strains will be a bigger challenge. It would not be practical or desirable to develop human challenge models for
M
all the known S. flexneri serotypes hence in vitro and/or in vivo assays may be the only realistic alternative. Animal models that have been used include rabbits, mice, guinea pigs and non-human primates. While all of these have limitations they are likely useful
pt ed
for early evaluations of vaccine candidates. Evaluating potential efficacy of Shigella vaccines using post immunization samples from humans has relied in large part on traditional methods such as ELISA or ELISPOT to measure O-antigen specific mucosal and systemic antibodies, although a correlate of protection has not been established. A
ce
different approach could be the use of functional antibody assays (12) to evaluate
Ac
efficacy.
Several live attenuated, inactivated whole cell and subunit vaccine candidates based on serotype protection are either in clinical trials or soon to undergo clinical evaluations. These trials offer timely opportunities to evaluate the potential for a much needed,
Downloaded from http://cid.oxfordjournals.org/ at University of Waikato Library on July 10, 2014
and S. flexneri 2a to test vaccine efficacy against these predominant endemic strains, and
6 broadly protective multivalent Shigella vaccine. The Livio study provides useful data for
The authors have no reported conflicts of interest.
REFERENCES
us
1. Diarrhoeal Diseases (Updated February 2009) page. World Health Organization website. Available at: http://www.who.int/vaccine_research/diseases/diarrhoeal/en/index.html.
an
2. Kotloff KL, Nataro JP, Blackwelder WC et al. Burden and aetiology of diarrhoeal disease in infants and young children in developing countries (the Global Enteric Multicenter Study, GEMS): a prospective, case-control study. Lancet 2013; Jul 20;382(9888):209-22
M
3. Carlin NI, Wehler T, Lindberg AA. Shigella flexneri O-antigen epitopes: chemical and immunochemical analyses reveal that epitopes of type III and group 6 antigens are identical. Infect Immun. 1986; Jul;53(1):110-5.
5.
pt ed
4. Liu B, Knirel YA, Feng L et al. Structure and genetics of Shigella O antigens. FEMS Microb. Review 2008; 32:627-653. Kenne L, Lindberg B, Petersson K et al. Structural studies of Shigella flexneri Oantigens. Eur J Biochem. 1978; 91(1):279-84.
6. Perepelov AV, Shekht ME, Liu B et al. Shigella flexneri O-antigens revisited: final elucidation of the O-acetylation profiles and a survey of the O-antigen structure diversity. FEMS Immunol Med Microbiol. 2012; 66(2):201-10
ce
7. Formal SB, Oaks EV, Olsen RE et al. Effect of prior infection with virulent Shigella flexneri 2a on the resistance of monkeys to subsequent infection with Shigella sonnei. J Infect Dis. 1991; 164(3):533-7
Ac
8. Mel D, Gangarosa EJ, Radovanovic ML et al. Studies on vaccination against bacillary dysentery. 6. Protection of children by oral immunization with streptomycin-dependent Shigella strains. Bull World Health Organ. 1971;45(4):457-64. 9.
von Seidlein L, Kim DR, Ali M et al. A multicentre study of Shigella diarrhoea in six Asian countries: disease burden, clinical manifestations, and microbiology. PLoS Med. 2006; 3(9):e353.
Downloaded from http://cid.oxfordjournals.org/ at University of Waikato Library on July 10, 2014
cr ipt
addressing the serotypic requirements for such an effective vaccine.
7 10. Toro CS, Farfán M, Contreras I et al. Genetic analysis of antibiotic-resistance determinants in multidrug-resistant Shigella strains isolated from Chilean children. Epidemiol Infect. 2005;133(1):81-6
cr ipt
11. Noriega FR, Liao FM, Maneval DR et al. Strategy for cross-protection among Shigella flexneri serotypes. Infect Immun. 1999;67(2):782-8.
an M pt ed ce Ac
Downloaded from http://cid.oxfordjournals.org/ at University of Waikato Library on July 10, 2014
us
12. Burton RL, Nahm MH. Development and validation of a fourfold multiplexed opsonization assay (MOPA4) for pneumococcal antibodies. Clin Vaccine Immunol. 2006;13(9):1004-9.
