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New Vaccine Development: Establishing Priorities: Volume II, Diseases of Importance in Developing Countries (1986)

Chapter: Appendix D-14: The Prospects for Immunizing Against Salmonella typhi

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Suggested Citation:"Appendix D-14: The Prospects for Immunizing Against Salmonella typhi." Institute of Medicine. 1986. New Vaccine Development: Establishing Priorities: Volume II, Diseases of Importance in Developing Countries. Washington, DC: The National Academies Press. doi: 10.17226/920.
×

Appendix D-14
The Prospects for Immunizing Against Salmonella typhi

DISEASE DESCRIPTION

Typhoid fever is an enteric fever caused by the bacterium Salmonella typhi. The disease is characterized by systemic symptoms of fever, malaise, and abdominal discomfort. A transient rash, splenomegaly, and leukopenia often occur. The major complications of the disease are intestinal hemorrhage, occurring in 2 to 8 percent of cases, and intestinal perforation, occurring in 3 to 4 percent of cases. The rate of mortality with the uncomplicated disease is generally low (less than 1 percent), especially if appropriate antibiotic treatment is provided; however, cases with severe illness and complications have a higher mortality rate (3 to 30 percent; Hornick, 1982).

Protection from disease by vaccination was first attempted at the end of the nineteenth century, and for the next 70 years efforts focused primarily on killed-parenteral vaccines. The history of these efforts has been comprehensively reviewed by Germanier (1984). Several varieties of killed, whole-cell parenteral S. typhi vaccines have been studied in field trials to determine safety and efficacy. These parenteral, whole-cell vaccines caused significant adverse reactions, including fever, malaise, and severe local pain and swelling. Because of the frequency of such reactions to parenteral typhoid vaccines, these vaccines have not been considered useful public health tools. Thus, the major thrust in the development of new immunizing agents against typhoid fever has been to identify agents that are at least equal in efficacy to the whole-cell parenteral vaccine, but that cause no adverse reactions (Germanier, 1984).

A candidate live attenuated vaccine based on S. typhi Ty21a is in an advanced stage of development.

The committee gratefully acknowledges the efforts of R.E.Black, who prepared major portions of this appendix, and the advice and assistance of P.A.Blake. The committee assumes full responsibility for all judgments and assumptions.

Suggested Citation:"Appendix D-14: The Prospects for Immunizing Against Salmonella typhi." Institute of Medicine. 1986. New Vaccine Development: Establishing Priorities: Volume II, Diseases of Importance in Developing Countries. Washington, DC: The National Academies Press. doi: 10.17226/920.
×

PATHOGEN DESCRIPTION

Salmonella typhi, an obligate intracellular pathogen, is the cause of typhoid fever. The organism is a gram-negative, nonsporing bacillus, actively motile with numerous long peritrichous flagellae. Other salmonellae, S.paratyphi A and B, cause paratyphoid fever, which is similar to typhoid fever but usually a milder disease clinically. These organisms can be differentiated based on their cultural characteristics. S. typhi and S. paratyphi have a strong host specificity for man and do not naturally infect animals. In most countries in which these diseases have been studied, the ratio of disease caused by S. typhi to that caused by S. paratyphi is about 10 to 1. (For further information on S.typhi, see Hornick, 1982, 1985.)

HOST IMMUNE RESPONSE

Infection with S. typhi confers some immunity, but second illnesses can occur following reexposure. It appears that immunity can be overwhelmed by the ingestion of a large number of S. typhi, as was suggested by studies in which volunteers with previously documented typhoid fever ingested 105S. typhi and had a clinical attack rate similar to that of a control group.

Several specific antibody responses have been demonstrated after typhoid fever. However, there is no evidence that these responses to O, H, and Vi antigens are protective against infection or illness. It is likely that secretory IgA is also produced in the small intestine, but this has not been well documented.

Animal models indicate that the cellular immune response probably is of primary importance in the protection against typhoid fever. Host defense relies on macrophage microbicidal mechanisms to kill phagocytosed bacteria. Enhancement of macrophage function is directed by specifically committed activated T-lymphocytes and controlled by a family of effector and regulatory T-cells. Current knowledge about immunity to S. typhi in humans does not permit more than general speculation about the way in which cell-mediated immunity is stimulated by either prior disease or a vaccine to prevent acute typhoid fever and its complications, or the development of the chronic carrier state (Germanier, 1984; Hornick, 1982, 1985; Levine et al., 1983).

DISTRIBUTION OF DISEASE

Geographic Distribution

Typhoid fever has worldwide distribution, but is especially prevalent in less-developed countries. Areas with environmental conditions conducive to the spread of the disease or with populations with a high prevalence of biliary tract disease and chronic carriage of S. typhi have higher rates of the disease (Germanier, 1984).

Suggested Citation:"Appendix D-14: The Prospects for Immunizing Against Salmonella typhi." Institute of Medicine. 1986. New Vaccine Development: Establishing Priorities: Volume II, Diseases of Importance in Developing Countries. Washington, DC: The National Academies Press. doi: 10.17226/920.
×

Disease Burden Estimates

Table D-14.1 shows the estimated incidence by age of typhoid fever cases in Africa, Asia, Latin America, and Oceania. Febrile, unrecognized cases of typhoid are assigned to morbidity category A; recognized moderate cases are assigned to category B; and recognized severe cases are assigned to category C. It is estimated that the number of mild cases of typhoid fever (probably undiagnosed) equals the number of recognized cases. It should be noted that the fatality rates in different regions vary: Table D-14.2 presents reported typhoid case-fatality rates in selected countries from 1951 to the present.

Figures from Table D-14.1 were used as a basis for the disease burden estimates in Table D-14.3.

PROBABLE VACCINE TARGET POPULATION

The incidence of clinically recognized typhoid fever appears to be highest in school-age children and young adults in endemic areas (Punjabi, 1984). Relatively few cases of typhoid fever are reported in children younger than 2 years of age in the same populations. There is some evidence that when these young children are exposed to S. typhi, they develop a bacteremic but clinically milder illness. Prospective studies of the age-specific incidence of the disease are needed to determine the best strategy for controlling endemic typhoid fever by vaccination. Additional information also is needed on the duration of protection afforded by such vaccines as Ty21a S. typhi and their efficacy when administered to young children.

It will be impossible to incorporate a typhoid fever vaccine into the existing World Health Organization Expanded Program on Immunization (WHO-EPI) if the primary target population is restricted to school-age children and young adults. However, if a candidate vaccine proves to be effective when given to small children and to have a long duration of protection (20 to 30 years), this situation could change. Development of a vaccine formulation other than enteric-coated capsules (which cannot be swallowed by infants and young children) will be necessary for this to happen. The calculation of vaccine benefits is based on the assumption that efforts in this direction will be successful.

Vaccine Preventable Illness*

Crude estimates indicate that at least 75 percent of the disease burden falls upon school-age children and young adults up to 34 years

*  

Vaccine preventable illness is defined as that portion of the disease burden that could be prevented by immunization of the entire target population (at the anticipated age of administration) with a hypothetical vaccine that is 100 percent effective (see Chapter 7).

Suggested Citation:"Appendix D-14: The Prospects for Immunizing Against Salmonella typhi." Institute of Medicine. 1986. New Vaccine Development: Establishing Priorities: Volume II, Diseases of Importance in Developing Countries. Washington, DC: The National Academies Press. doi: 10.17226/920.
×

TABLE D-14.1 Estimated Typhoid Fever Cases in the Developing World by Region and Age Group

Region

Total Population (millions)

Incidence of Recognized Typhoid Fever per 100,000 (all ages)

Total Number of Moderate and Severe Cases

Number of Moderate Cases (0.67)

Number of Severe Cases (0.33)

Fatality Ratec (percent of severe cases)

Number of Deaths

Number of Mild Cases (febrile-unrecognized)

Africa

531

500a

2,655,000

1,778,850

876,150

15

131,422

2,655,000

Asia

2,662

500a

13,310,000

8,917,700

4,392,300

10

439,230

13,310,000

Latin America

397

150b

595,500

398,985

196,515

5

9,826

595,500

Oceania

5

150b

7,500

5,025

2,475

5

124

7,500

Total

 

 

16,568,000

11,100,560

5,467,440

 

580,602

16,568,000

NOTE: Percentage of cases by age group: under 5 is 6 percent; 5–14 is 37 percent; 15–59 is 55 percent; 60 and over is 2 percent.

aBased on India (540, 543, and 634) and Indonesia (450).

bBased on Chile (110).

cPunjabi (1984)

Suggested Citation:"Appendix D-14: The Prospects for Immunizing Against Salmonella typhi." Institute of Medicine. 1986. New Vaccine Development: Establishing Priorities: Volume II, Diseases of Importance in Developing Countries. Washington, DC: The National Academies Press. doi: 10.17226/920.
×

TABLE D-14.2 Typhoid Incidence and Case-Fatality Rates (CFR)

Location

Year

Patient Population

Number of Cases of Typhoid Fever

Deaths

CFR (percent)

South Korea

1951

U.S. and United Nations soldiers

81,575

14,051

17

Indonesia

1950

Hospitalized Indonesians

17

1

6

Egypt

1950

Hospitalized Egyptians

200

13

7

South Africa

1951

Hospitalized South Africans

139

17

12

India

1953

Hospitalized Indians

1,064

180

17

Iran

1954–1967

Hospitalized Iranian children

35

3

8

India

1959–1965

Hospitalized Indians

340

19

6

South Africa

1959–1967

Hospitalized South African children

298

21

7

Nigeria

1959–1970

Hospitalized Nigerians

959

172

18

Iran

1961

Hospitalized Iranians

530

19

4

Indonesia

1961

Hospitalized Indonesian children

68

4

6

India

1967

Hospitalized Indians

98

13

13

India

1969–1970

Hospitalized Indians

100

7

7

Ethiopia

1975–1980

Hospitalized Ethiopians

50

6

12

Nigeria

1972–1978

Hospitalized Nigerian children

101

32

32

Indonesia

1971–1972

Hospitalized Indonesians

188

28

15

South Vietnam

1971–1974

Hospitalized Vietnamese

101

8

8

Indonesia

1977–1978

Hospitalized Indonesians

60

7

12

Indonesia

1976–1979

Hospitalized Indonesians

542

46

9

India

1977–1982

Hospitalized Indians

410

73

18

Indonesia

1980

Hospitalized Indonesians

33

6

18

 

SOURCE: Punjabi (1984).

Suggested Citation:"Appendix D-14: The Prospects for Immunizing Against Salmonella typhi." Institute of Medicine. 1986. New Vaccine Development: Establishing Priorities: Volume II, Diseases of Importance in Developing Countries. Washington, DC: The National Academies Press. doi: 10.17226/920.
×

TABLE D-14.3 Disease Burden: Salmonella typhi

 

 

 

Under 5 Years

5–14 Years

15–59 Years

60 Years and Over

Morbidity Category

Description

Condition

Number of Cases

Duration

Number of Cases

Duration

Number of Cases

Duration

Number of Cases

Duration

A

Moderate localized pain and/or mild systemic reaction, or impairment requiring minor change in normal activities, and associated with some restriction of work activity

Malaise, mild fever

994,080

3

6,130,160

3

9,112,400

3

331,360

3

B

Moderate pain and/or moderate impairment requiring moderate change in normal activities, e.g., housebound or in bed, and associated with temporary loss of ability to work

Moderate fever, abdominal pain

666,034

6

4,107,207

6

6,105,308

6

222,011

6

C

Severe pain, severe short term impairment, or hospitalization

Fever, intestinal hemorrhage

328,046

12

2,022,953

12

3,007,092

12

109,349

12

D

Mild chronic disability (not requiring hospitalization, institutionalization, or other major limitation of normal activity, and resulting in minor limitation of ability to work)

 

 

n.a.

 

n.a.

 

n.a.

 

n.a.

E

Moderate to severe chronic disability (requiring hospitalization, special care, or other major limitation of normal activity, and seriously restricting ability to work)

 

 

n.a.

 

n.a.

 

n.a.

 

n.a.

F

Total impairment

 

 

n.a.

 

n.a.

 

n.a.

 

n.a.

G

Reproductive impairment resulting in infertility

 

 

n.a.

 

n.a.

 

n.a.

 

n.a.

H

Death

 

34,836

n.a.

214,823

n.a.

319,331

n.a.

11,612

n.a.

Suggested Citation:"Appendix D-14: The Prospects for Immunizing Against Salmonella typhi." Institute of Medicine. 1986. New Vaccine Development: Establishing Priorities: Volume II, Diseases of Importance in Developing Countries. Washington, DC: The National Academies Press. doi: 10.17226/920.
×

of age. However, if all preschool children could be vaccinated with a vaccine that provided 100 percent protection over a long period, it would be possible to eliminate 100 percent of the disease. This assumption, adopted for calculations, assumes that a formulation acceptable and effective in infants and young children can be developed.

SUITABILITY FOR VACCINE CONTROL

Typhoid fever appears to be quite suitable for vaccine control, especially given the possibility of vaccines developed from oral, nonreactogenic strains of S. typhi, such as Ty21a. Such a vaccine probably could be delivered before the youngest age at which disease occurs.

If the new vaccine prevents people from becoming carriers, benefits would be extended to unvaccinated individuals because of reduced exposure.

Alternative Control Measures and Treatments

There is no animal host or environmental reservoir of S. typhi. Patients with typhoid fever, asymptomatic transient carriers, and chronic carriers are the only sources of infection. S. typhi can be spread by either food or water. Alternative strategies to prevent disease would be to reduce the number of infected persons, including carriers, and to ensure that food and water are not contaminated by them or are not consumed by susceptible persons. In many areas of the world, these strategies are not feasible at this time.

Effective antibiotic treatment with chloramphenicol, co-trimoxazole, or other drugs can shorten the duration of disease and reduce the mortality rate. However, in some areas the mortality rate remains high despite effective antibiotic treatment. It recently has been demonstrated that the death of some severely ill patients can be prevented by the use of high-dose corticosteroids in combination with antibiotics. In addition, management of hospitalized patients requires attention to nutrition, fluid and electrolyte balance, and prompt treatment of complications, such as intestinal perforation or bleeding.

PROSPECTS FOR VACCINE DEVELOPMENT

Two comprehensive reviews have recently dealt with vaccines directed against S. typhi. Germanier (1984) has described the history of efforts to date to develop effective vaccines against S. typhi and provides a detailed account of trials on the live attenuated strain Ty21a. Levine et al. (1983) dealt with this and other vaccine candidates under development. Therefore, this section is a brief overview of these vaccines; further details on specific candidates can be found in these two publications.

Suggested Citation:"Appendix D-14: The Prospects for Immunizing Against Salmonella typhi." Institute of Medicine. 1986. New Vaccine Development: Establishing Priorities: Volume II, Diseases of Importance in Developing Countries. Washington, DC: The National Academies Press. doi: 10.17226/920.
×

Of the killed whole-cell parenteral S. typhi vaccines, the acetone-killed typhoid vaccine is perhaps the best. In field trials in Guyana, two subcutaneous doses of the vaccine provided about 88 percent efficacy for at least 7 years (Germanier, 1984). Because of the frequency of adverse reactions, such as fever, malaise, and abdominal pain, this vaccine has not been widely used.

One relatively new approach for a typhoid vaccine has involved the use of purified Vi antigen as a parenteral vaccine. In initial safety testing, it appeared that this vaccine did not elicit severe adverse reactions and that it stimulated high titers of circulating IgG Vi antibody (Levin et al., 1975; Wong et al., 1974). It was postulated that such antibody would prevent the primary bacteremia, during which the reticuloendothelial system becomes seeded with S. typhi after penetration of the intestine. However, in further studies with the purified Vi vaccine, nearly half of the vaccinees had a moderate or severe systemic reaction, and 8 percent had fever. The reaction rate was similar to that of the whole-cell parenteral typhoid fever vaccine. Furthermore, sera from volunteers given the purified Vi vaccine showed rises in antibody to S. typhi lipopolysaccharide, indicating that the vaccine was contaminated with small amounts of this antigen.

Another approach has been the development of live attenuated strains of S. typhi. One such vaccine candidate that showed initial promise was the streptomycin-dependent mutant of S. typhi. In volunteer studies, this oral attenuated vaccine was well tolerated and highly protective against experimental challenge. However, when lyophilized vaccine was given, no protection was conferred. Because a lyophilized vaccine formulation is required for field studies and eventual use, further studies with this strain were abandoned (Germanier, 1984).

An important advance was the development of the attenuated ga1E mutant S. typhi strain Ty21a, developed by Dr. Rene Germanier (Germanier and Furer, 1975). This mutant is devoid of the enzyme UDP-galactose-4-epimerase and shows reduced activity of two other enzymes. Grown in the presence of galactose, smooth lipopolysaccharide O antigen is produced. However, because of its lack of epimerase, strain Ty21a accumulates intermediate products of metabolism, which results in bacterial lysis. Studies in North American volunteers and field trials in Egypt and Chile have demonstrated that this vaccine is safe and easily administered orally (Germanier, 1984). Recent results from field trials in Santiago, Chile, showed that three doses of the vaccine contained within enteric-coated capsules provided about 75 percent protection for at least 1 year (National Institute of Allergy and Infectious Diseases, 1985).

Another method of attenuation that has been used for Salmonella typhimurium and that could perhaps be applied to S. typhi is to derive aromatic amino acid-dependent strains of bacteria (Hoiseth and Stocker, 1981; Stocker et al., 1983). Some auxotrophic mutants that require a metabolite not available in vertebrate tissue would be unable to grow in such tissues and thus would be nonvirulent. Such strains of S. typhimurium have been examined in calves. The vaccine was given

Suggested Citation:"Appendix D-14: The Prospects for Immunizing Against Salmonella typhi." Institute of Medicine. 1986. New Vaccine Development: Establishing Priorities: Volume II, Diseases of Importance in Developing Countries. Washington, DC: The National Academies Press. doi: 10.17226/920.
×

orally or parenterally, and 3 weeks later the vaccinated and control calves were challenged orally with pathogenic S. typhimurium (Robertsson et al., 1983). The oral attenuated vaccine protected significantly better than the parenteral killed vaccine. These results are sufficiently promising to evoke interest in analogous aromatic-dependent S. typhi oral vaccine strains for human use.

New vaccines to protect against typhoid fever, particularly the live oral vaccines, provide an opportunity for the disease control in endemic areas. However, further vaccine studies are impeded by the lack of understanding of the immunological basis of protection and the lack of suitable animal models for typhoid fever. At this point, the only way to assess the efficacy of a vaccine is through large-scale field trials in endemic areas.

REFERENCES

Germanier, R. 1984. Typhoid fever. Pp. 137–165 in Bacterial Vaccines, R.Germanier, ed. New York: Academic Press.

Germanier, R., and E.Furer. 1975. Isolation and characterization of S. typhi gal E mutant Ty21a: A candidate strain for a live oral typhoid vaccine. J. Infect. Dis. 131:553–558.


Hoiseth, S.K., and B.A.D.Stocker. 1981. Aromatic dependent Salmonella typhimurium are non-virulent and effective as live vaccines. Nature 291:238.

Hornick, R.B. 1982. Typhoid fever. Pp. 659–676 in Bacterial Infections of Humans, A.S.Evans and H.A.Feldman, eds. New York: Plenum.

Hornick, R.B. 1985. Selective primary health care: strategies for the control of diseases in the developing world. XX. Typhoid fever. Rev. Infect. Dis. 7:536–546.


Levin, D.M., K.H.Wong, H.V.Reynolds, A.Sutton, and R.S.Northrup. 1975. Vi antigen from Salmonella typhosa and immunity against typhoid fever. II. Safety and immunogenicity in humans. Infect. Immun. 12:1290–1294.

Levine, M.M., J.B.Kaper, R.E.Black, and M.L.Clements. 1983. New knowledge on pathogenesis of bacterial enteric infections as applied to vaccine development. Microbiol. Rev. 47:510–550.


National Institute of Allergy and Infectious Diseases. 1985. Program on Accelerated Development of New Vaccines. Progress Report. Bethesda, Md.: National Institutes of Health.


Punjabi, N.H. 1984. Paper presented at the International Workshop on Typhoid Fever, Pan American Health Organization, Washington, D.C., November 29–30, 1984.


Robertsson, J.A., A.A.Lindberg, S.Hoiseth, and B.A.D.Stocker. 1983. Salmonella typhimurium infection in calves: Protection and survival of virulent challenge bacteria after immunization with live or inactivated vaccines. Infect. Immun. 41:742–750.

Suggested Citation:"Appendix D-14: The Prospects for Immunizing Against Salmonella typhi." Institute of Medicine. 1986. New Vaccine Development: Establishing Priorities: Volume II, Diseases of Importance in Developing Countries. Washington, DC: The National Academies Press. doi: 10.17226/920.
×

Stocker, B.A.D., S.K.Hoiseth, and B.D.Smith. 1983. Aromatic dependent “salmonella sp” as live vaccine in mice and calves. Dev. Biol. Stand. 53:47–54.


Wong, K.H., J.C.Feeley, R.S.Northrup, and M.K.Forlines. 1974. Viantigen from Salmonella typhosa and immunity to typhoid fever. I. Isolation and immunologic properties in animals. Infect. Immun. 9:348–353.

Suggested Citation:"Appendix D-14: The Prospects for Immunizing Against Salmonella typhi." Institute of Medicine. 1986. New Vaccine Development: Establishing Priorities: Volume II, Diseases of Importance in Developing Countries. Washington, DC: The National Academies Press. doi: 10.17226/920.
×
Page 319
Suggested Citation:"Appendix D-14: The Prospects for Immunizing Against Salmonella typhi." Institute of Medicine. 1986. New Vaccine Development: Establishing Priorities: Volume II, Diseases of Importance in Developing Countries. Washington, DC: The National Academies Press. doi: 10.17226/920.
×
Page 320
Suggested Citation:"Appendix D-14: The Prospects for Immunizing Against Salmonella typhi." Institute of Medicine. 1986. New Vaccine Development: Establishing Priorities: Volume II, Diseases of Importance in Developing Countries. Washington, DC: The National Academies Press. doi: 10.17226/920.
×
Page 321
Suggested Citation:"Appendix D-14: The Prospects for Immunizing Against Salmonella typhi." Institute of Medicine. 1986. New Vaccine Development: Establishing Priorities: Volume II, Diseases of Importance in Developing Countries. Washington, DC: The National Academies Press. doi: 10.17226/920.
×
Page 322
Suggested Citation:"Appendix D-14: The Prospects for Immunizing Against Salmonella typhi." Institute of Medicine. 1986. New Vaccine Development: Establishing Priorities: Volume II, Diseases of Importance in Developing Countries. Washington, DC: The National Academies Press. doi: 10.17226/920.
×
Page 323
Suggested Citation:"Appendix D-14: The Prospects for Immunizing Against Salmonella typhi." Institute of Medicine. 1986. New Vaccine Development: Establishing Priorities: Volume II, Diseases of Importance in Developing Countries. Washington, DC: The National Academies Press. doi: 10.17226/920.
×
Page 324
Suggested Citation:"Appendix D-14: The Prospects for Immunizing Against Salmonella typhi." Institute of Medicine. 1986. New Vaccine Development: Establishing Priorities: Volume II, Diseases of Importance in Developing Countries. Washington, DC: The National Academies Press. doi: 10.17226/920.
×
Page 325
Suggested Citation:"Appendix D-14: The Prospects for Immunizing Against Salmonella typhi." Institute of Medicine. 1986. New Vaccine Development: Establishing Priorities: Volume II, Diseases of Importance in Developing Countries. Washington, DC: The National Academies Press. doi: 10.17226/920.
×
Page 326
Suggested Citation:"Appendix D-14: The Prospects for Immunizing Against Salmonella typhi." Institute of Medicine. 1986. New Vaccine Development: Establishing Priorities: Volume II, Diseases of Importance in Developing Countries. Washington, DC: The National Academies Press. doi: 10.17226/920.
×
Page 327
Suggested Citation:"Appendix D-14: The Prospects for Immunizing Against Salmonella typhi." Institute of Medicine. 1986. New Vaccine Development: Establishing Priorities: Volume II, Diseases of Importance in Developing Countries. Washington, DC: The National Academies Press. doi: 10.17226/920.
×
Page 328
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Common diseases cost the developing world an enormous amount in terms of human life, health, and productivity, as well as lost economic potential. New and effective vaccines could not only improve the quality of life for millions of residents in developing countries, they could also contribute substantially to further economic development. Using data from the World Health Organization and other international agencies, this book analyzes disease burdens, pathogen descriptions, geographic distribution of diseases, probable vaccine target populations, alternative control measures and treatments, and future prospects for vaccine development. New Vaccine Development provides valuable insight into immunological and international health policy priorities.

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