The role of epidemiology in the introduction of vi polysaccharide typhoid fever vaccines in Asia

Despite the availability of at least two licensed typhoid fever vaccines--injectable sub-unit Vi polysaccharide vaccine and live, oral Ty21a vaccine--for the last decade, these vaccines have not been widely introduced in public-health programmes in countries endemic for typhoid fever. The goal of the multidisciplinary DOMI (Diseases of the Most Impoverished) typhoid fever programme is to generate policy-relevant data to support public decision-making regarding the introduction of Vi polysaccharide typhoid fever immunization programmes in China, Viet Nam, Pakistan, India, Bangladesh, and Indonesia. Through epidemiological studies, the DOMI Programme is generating these data and is offering a model for the accelerated, rational introduction of new vaccines into health programmes in low-income countries. Practical and specific examples of the role of epidemiology are described in this paper. These examples cover: (a) selection of available typhoid fever vaccines to be introduced in the programme, (b) generation of policy-relevant data, (c) providing the 'backbone' for the implementation of other multidisciplinary projects, and (d) generation of unexpected but useful information relevant for the introduction of vaccines. Epidemiological studies contribute to all stages of development of vaccine evaluation and introduction.     

Vaccines against typhoid fever

Because of high infectivity and significant disease burden, typhoid fever constitutes a major global health problem. Implementation of adequate food handling practices and establishment of safe water supplies are the cornerstone for the development of an effective prevention program. However, vaccination against typhoid fever remains an essential tool for the effective management of this disease. Currently, there are two well tolerated and effective licensed vaccines. One is based on defined subunit virulence (Vi) polysaccharide antigen and can be administered either intramuscularly or subcutaneously and the other is based on the use of live attenuated bacteria for oral administration. The advantages and disadvantages of the various approaches taken in the development of a vaccine against typhoid fever are discussed, along with the potential for future vaccine candidates.     

Is it time for a new yellow fever vaccine?

An inexpensive live attenuated vaccine (the 17D vaccine) against yellow fever has been effectively used to prevent yellow fever for more than 70 years. Interest in developing new inactivated vaccines has been spurred by recognition of rare but serious, sometimes fatal adverse events following live virus vaccination. A safer inactivated yellow fever vaccine could be useful for vaccinating people at higher risk of adverse events from the live vaccine, but could also have broader global health utility by lowering the risk-benefit threshold for assuring high levels of yellow fever vaccine coverage. If ongoing trials demonstrate favorable immunogenicity and safety compared to the current vaccine, the practical global health utility of an inactivated vaccine is likely to be determined mostly by cost.     

Policymakers' views regarding the introduction of new-generation vaccines against typhoid fever, shigellosis and cholera in Asia

Face-to-face interviews and meetings with more than 160 policymakers and other influential professionals in seven large Asian countries (Bangladesh, China, India, Indonesia, Pakistan, Thailand and Vietnam) were conducted to survey opinions regarding the need for, and potential uses of new-generation vaccines against cholera, typhoid fever and shigellosis. Despite several barriers to their uptake--notably uncertainty of the burden of enteric diseases; preference for water, sanitation and other environmental improvements over vaccination for disease control; and high prices of the current vaccines relative to basic EPI vaccines, and their moderate protection levels--considerable interest was found in the targeted use of Vi typhoid vaccine in most countries, followed by (future) Shigella and oral cholera vaccines. The introduction of these vaccines in Asia could be greatly facilitated by country-specific evidence of disease burden, local or regional vaccine production, field studies demonstrating their safety and efficacy in local populations, evidence of potential economic savings from vaccination, and effective dissemination of research results to all those who make or influence immunization policy.     

Vaccination of active component US military personnel against Salmonella Typhi

IntroductionVaccination against Salmonella Typhi is one of the leading public health interventions reducing the risk of typhoid fever. There are two available licensed vaccines, Vivotif, oral live-attenuated, and Typhim Vi, intramuscular Vi capsular polysaccharide. The US military is a high risk travel population commonly vaccinated for S. Typhi. We describe the use of S. Typhi vaccination in this population and the acute reactogenicity profile of these vaccines.MethodsData were obtained from the Defense Medical Surveillance System and vaccination identified between 1998 and 2011 from vaccination codes. Clinical outcomes were assessed for four weeks post vaccination. Adverse event rates and odds ratios were estimated across the two vaccine types.ResultsA total of 1.9 million predominately male military personnel received 3.6 million S. Typhi vaccinations with 94.3% of vaccinees receiving the Vi capsule vaccine though variability in the vaccine administered was observed. Receipt of other vaccinations in the 6 months surrounding the S. Typhi vaccine was common. Rates of nausea (195 per 100,000 vaccinations), headache (13 per 100,000 vaccinations) and fever (40 per 100,000 vaccinations) were significantly higher following Vi capsule vaccination compared to receipt of Vivotif (130, 2, 10 per 100,000 vaccinations, respectively). In contrast the rates of rash and non-infectious diarrhea (186 and 426 per 100,000 vaccinations, respectively) were increased in those receiving Vivotif compared to the Vi capsule vaccine.DiscussionThe US military is a major consumer of S. Typhi vaccines. The parenterally administered vaccine appears to be more amenable, though we were limited in our ability to assess the reasons for its higher usage. While we observed a higher rate of several adverse events in subjects receiving the intramuscular vaccination, the overall rate of these events was low. Future studies assessing more long-term health outcomes are warranted.     

A review of vaccine research and development: human enteric infections

Worldwide, enteric infections rank third among all causes of disease burden, being responsible for some 1.7-2.5 million deaths per year, mostly in young children and infants in developing countries. The main infectious agents responsible for human enteric infections include several viruses (enteric adenoviruses, astroviruses, human caliciviruses (HuCV), rotaviruses (RV)) and several bacterial agents, such as Campylobacter jejuni, a variety of pathogenic Escherichia coli strains including enterotoxigenic E. coli (ETEC), several Shigella species, various Salmonella strains including S. typhi and S. paratyphi, the agents of typhoid fever, and Vibrio cholerae, the agent of cholera. While effective vaccines are available at present against typhoid fever and cholera, no vaccine is available against illnesses caused by HuCV, Campylobacter, ETEC or the Shigellae. Rotavirus vaccines have had more success, although RV disease prevention suffered a major setback in 1999 with the withdrawal of a live simian-human reassortant RV vaccine less than a year after its introduction. New live oral RV vaccines have now been developed and are or should presently be ready for licensure. This article reviews the state of the art in vaccine R&D against human viral and bacterial enteric infections of public health importance.     

Vi-CRM 197 as a new conjugate vaccine against Salmonella Typhi

An efficacious, low cost vaccine against typhoid fever, especially for young children, would make a major impact on disease burden in developing countries. The virulence capsular polysaccharide of Salmonella Typhi (Vi) coupled to recombinant mutant Pseudomonas aeruginosa exoprotein A (Vi-rEPA) has been shown to be highly efficacious. We investigated the use of carrier proteins included in infant vaccines, standardized the conjugation process and developed key assays required for routine lot release at production scale. Vi from a BSL1 organism, Citrobacter freundii, strain WR7011, was used as an alternative to Vi from S. Typhi. We showed that Vi conjugated to CRM₁₉₇, a non-toxic mutant of diphtheria toxin, widely used in commercial vaccines, was produced at high yield. Vi-CRM₁₉₇ proved immunogenic in animal studies, even without adjuvant. Thus, Vi-CRM₁₉₇ appears to be a suitable candidate for the development of a commercially viable, effective typhoid vaccine for developing countries.     

Vaccination of patients with diabetes mellitus--a retrospective study

402 subjects with diabetes mellitus have been vaccinated of the total of 34,000 vaccinees immunized during the study period of 9 and half months. Altogether 229 diabetic patients (56.97%) have been vaccinated'against tick-borne encephalitis (TBE) and 74 (18.4%) against viral hepatitis (41 types A+B, 30 type A, 3 type B). The average age in four most commonly administered vaccines (FSME IMMUN 0.5 ML, Twinrix Adult, Typhim Vi, and Havrix 1440) was 65, 52, 56, and 54 years, respectively. Live attenuated vaccines have been given to 6 patients with diabetes (1.49%)--- 5 travellers to endemic countries received the yellow fever vaccine Stamaril (1 female, 4 male) and one male patient varicella vaccine Varilrix. Among the least common vaccines in diabetic patients were those against invasive pneumococcal and meningococcal infections. Not a single unexpected side effect has been observed following the vaccination procedure in any diabetic patient. Based on the results of this retrospective study we can conclude that vaccination in diabetic patients is free of any ri-k- provided that there are no other contraindications, e.g. allergy to vaccine components or severe acute febrile illness. In the case of unstable glycaemia and significantly impaired immune system due to diabetes mellitus, vaccination with live attenuated vaccines should be carefully considered and measured against the risks of exposure to each and every specific infectious agent. There is no reason to be afraid of vaccination in diabetic patients provided that general contraindications are respected. On the contrary, this risk group can benefit from vaccination more remarkably since it may have some life-saving potential.     

Next-generation rotavirus vaccine developers meeting: Summary of a meeting sponsored by PATH and the bill & melinda gates foundation (19–20 June 2019, Geneva)

Despite the contribution of currently licensed live, oral rotavirus vaccines (LORVs) to alleviating the burden of severe disease and death from rotavirus gastroenteritis, those vaccines have proven less efficacious in resource-limited settings than in high- and middle-income countries. It has been proposed that the residual burden of rotavirus disease might be overcome with parenterally administered vaccines, or next-generation rotavirus vaccines (NGRV). To better define the progress of development of these vaccines, a meeting of vaccine developers and manufacturers engaged in NGRV research and development was convened in Geneva in June 2019. Several NRGVs are in various stages of preclinical development, and two have already entered clinical testing. The vaccine platforms include subunit protein, inactivated whole virus, virus-like particle and RNA-based vaccines. Meeting participants included groups involved in NGRV development, scientists investigating correlates of protection of rotavirus vaccines, and representatives of international organizations with insight into considerations for vaccine introduction. This report summarizes the presentations shared at the meeting.     

Considerations for development of whole cell bacterial vaccines to prevent diarrheal diseases in children in developing countries

Enteric pathogens constitute a major pediatric threat in the developing world through their impact on morbidity and mortality, physical and cognitive development and cause and effect relationship with malnutrition. Although many bacterial pathogens can cause diarrheal diseases, a group of less than 10 including Shigella spp., enterotoxigenic Escherichia coli (ETEC), Vibrio cholerae, and possibly, Campylobacter jejuni account for a significant percentage of these diseases in developing countries. Rotavirus is also a major cause of diarrheal diseases. Vaccines against these agents offer a potentially effective control measure against these diseases, but safe, practical, and effective vaccines for many of these agents have yet to be realized. Many vaccine development approaches are under investigation, but the one that is currently most advanced and that has been most widely applied to enteric pathogens is the use of orally administered live or killed whole pathogen preparations. If inactivated, these vaccines will probably be administered as multiple doses with approximately 10(10) to 10(11) total particles per dose, but they are relatively safe for oral administration. Further, they may not require a buffer for delivery and can be stored in liquid formulations. Fewer doses may be required for some live attenuated pathogen vaccines, but a buffer will most likely be required for oral delivery and the product must be stored in a dried formulation. Also, safety becomes more of a concern with live pathogens depending on the degree of attenuation, host immunocompetence, and the total number and kinds of attenuated pathogens which may be present in a combined agent vaccine. Both live and killed whole pathogen vaccines can be immunogenic and have the possibility to serve as vectors for other antigens. Although many organisms and serotypes are clinically important, by exploiting antigenic cross reactivity and using some pathogen components as vectors for cloned antigens of other pathogens, it could be possible to induce immunity against major enteric pathogens/serotypes with <10 whole pathogen components in a multi-agent vaccine. Safe and effective mucosal adjuvants may in the future be useful in whole pathogen vaccines, but they do not seem to be essential for immunization. Further, dietary supplements such as zinc, mixed routes of delivery and new regimens are under study which may in the future enhance further the effectiveness of the whole pathogen vaccines which now seem realizable in the near term. For this to happen, however, a coordinated and committed effort is necessary now to address the immunologic, regulatory, manufacturing, testing and implementation issues which will be involved in the realization of this important product to benefit children's health worldwide.     

The current status of diarrhoea related vaccines

Since diarrhea is responsible for considerable morbidity and mortality in India as well as in developing and developed countries, public health specialists strive to develop vaccines against various pathogens which cause diarrhea. Rotavirus (RV) causes 20-40% of severe diarrhea among 6-24 month olds. So they hope for a single dose vaccine against all 4 RV serotypes which can be administered to newborns, but such a vaccine does not yet exist. The bovine and rhesus vaccines are the only heterologous candidate vaccines available, (as of the end of 1989). Another candidate vaccine is the human-animal reassortant RV vaccine where scientists incorporate the VP7 surface protein of human RV into animal RV. The 3rd type of RV candidate vaccine include the naturally attenuated human RV (nursery strains). Vibrio cholerae also causes significant diarrhea in India. Researchers have conducted field trials of many cholera vaccines since the mid 1990s, but they could not find a vaccine which could be used for mass vaccination against cholera. In fact, the cholera vaccine currently used only provides 50% protection, lasts 3-6 months, does not affect carriers, and does not protect against all strains. Salmonella typhi also causes diarrhea, especially among school age children and young adults. The results of large scale field trials in the 1960s reveal that 2 doses of the acetone inactivated typhoid vaccine performed the best of the injectable killed whole cell vaccines. In fact, it provides 79-93% protection and lasts 3-4 years. Further the live oral Ty21a lyophilized vaccine reconstituted in a liquid form and given in multiple doses provides comparable protection (71-96%) against typhoid as well as some protection against paratyphoid. Moreover they induce no side effects. Shigella species also cause diarrhea, especially in children. Various candidate vaccines against shigellosis include the spontaneously attenuated vaccines, streptomycin dependent vaccines, toxoid against exotoxins, and mutant hybrid strains.     

From research to phase III: preclinical, industrial and clinical development of the Sanofi Pasteur tetravalent dengue vaccine

Dengue vaccine development has reached a major milestone with the initiation, in 2010, of the first phase III clinical trial to investigate the Sanofi Pasteur CYD tetravalent dengue vaccine (TDV). The CYD TDV candidate is composed of four recombinant, live, attenuated vaccines (CYD-1-4) based on a yellow fever vaccine 17D (YFV 17D) backbone, each expressing the pre-membrane and envelope genes of one of the four dengue virus serotypes. The vaccine is genetically and phenotypically stable, non-hepatotropic, less neurovirulent than YFV 17D, and does not infect mosquitoes by the oral route. In vitro and in vivo preclinical studies showed that CYD TDV induces controlled stimulation of human dendritic cells, and significant immune responses in monkeys. Scale up and industrialization are being conducted in parallel with preclinical and clinical development to fulfill the needs of phase II/III trials, and to anticipate and facilitate supply and access to vaccine in the countries where the dengue disease burden makes it an urgent public health priority. The vaccine has now been administered to more than 6000 children and adults from dengue endemic and non-endemic areas and no safety concerns have arisen in any of the completed or ongoing trials. A three-dose vaccination regimen induces an immune response against all four serotypes in the large majority of vaccinees. Preexisting flavivirus immunity favors quicker and higher immune responses to CYD TDV, without adversely effecting clinical safety or increasing vaccine viremia. The observed level and nature of the cellular immune responses in humans are consistent with the good safety and immunogenicity profile of the vaccine. Preliminary results of an ongoing, proof-of-concept efficacy and large scale safety study in Thai children are expected by the end of 2012. Here we discuss the different steps and challenges of developing CYD TDV, from research to industrialization, and summarize some of the challenges to the successful introduction of a dengue vaccine into immunization programs.     

A bivalent vaccine to protect against Streptococcus pneumoniae and Salmonella typhi

Pneumococcal and Salmonella typhi infections are two major diseases for children in developing countries. For typhoid fever, licensed Vi polysaccharide vaccines are ineffective in children <2-year old. While investigational Vi conjugate vaccines have been shown effective in clinical trials, they are currently only available to restricted areas. Pneumococcal capsular polysaccharide conjugate vaccines are highly effective in children, but suffer from some limitations including cost and limited serotype coverage. We have previously shown that a fusion conjugate vaccine, consisting of pneumococcal fusion protein PsaA and pneumolysoid (PdT) conjugated to a polysaccharide, results in enhanced antibody and CD4+ Th17 cell responses as well as protection against pneumococcal colonization and disease in mice. Here we applied this approach to develop a bivalent vaccine against pneumococcus and S. typhi. Two species-conserved pneumococcal antigens (SP1572 or SP2070) were fused to the nonhemolytic pneumolysoid PdT. SP1572-PdT was then conjugated to Vi polysaccharide and SP2070-PdT was conjugated to the pneumococcal cell wall polysaccharide (CWPS; also conserved). Mice immunized with this bivalent conjugate were protected against pneumococcal colonization and sepsis challenges, and made anti-Vi antibody concentrations higher by 40-fold compared to mice that received equimolar mixtures of the antigens. An enhanced killing of Vi-bearing Salmonellae in vitro was demonstrated from plasma of mice that received the fusion conjugate but not the mixture of antigens. Our results support further evaluation of this bivalent immunogen for the prevention of pneumococcal colonization and disease, and of typhoid fever.     

The future control of rotavirus disease: Can live oral vaccines alone solve the rotavirus problem?

Live oral rotavirus (RV) vaccines used worldwide are most effective in reducing diarrheal hospitalizations from RV in high income countries and least effective in low income countries where RV remains a prime cause of death in children. Research has failed to fully explain the reason for this difference of efficacy for RV vaccines, an observation made with other live oral vaccines for polio, cholera and typhoid fever. Use of parenteral vaccines have been successful in overcoming this problem for both polio and typhoid and parenteral RV vaccines are now in development. This approach should be pursued for rotavirus vaccine as well because in low income countries where oral RV vaccines have been introduced and are only partially effective, RV remains the most common cause of diarrhea in children under 5 years. The ultimate control of RV diarrheal will likely require both oral and parenteral vaccines.     

Preparation and testing of a Vi conjugate vaccine using pneumococcal surface protein A (PspA) from Streptococcus pneumoniae as the carrier protein

In the current study pneumococcal surface protein A (PspA) was conjugated to Vi capsular polysaccharide from Salmonella Typhi to make available a vaccine against typhoid fever that has the potential to also provide broad protection from Streptococcus pneumoniae. High yielding production processes were developed for the purification of PspAs from families 1 and 2. The purified PspAs were conjugated to Vi with high recovery of both Vi and PspA. The processes developed especially for PspA family 2 could readily be adapted for large scale production under cGMP conditions. Previously we have shown that conjugation of diphtheria toxoid (DT) to Vi polysaccharide improves the immune response to Vi but can also enhance the response to DT. In this study it was shown that conjugation of PspA to Vi enhanced the anti-PspA response and that PspA was a suitable carrier protein as demonstrated by the characteristics of a T-cell dependent response to the Vi. We propose that a bivalent vaccine consisting of PspA from families 1 and 2 bound to Vi polysaccharide would protect against typhoid fever and has the potential to also protect against pneumococcal disease and should be considered for use in developing countries.     

A combined dual-chamber typhoid/hepatitis A vaccine as a booster dose in hepatitis A primed adults

Vivaxim™ is a combined hepatitis A/typhoid fever vaccine (HA/Vi) licensed for vaccination of travellers, but long-term protection against hepatitis A requires two immunisations at least 6 months apart. A randomised, controlled study was performed in 116 healthy adults primed with hepatitis A vaccine (Avaxim™) to compare immune responses to HA/Vi and Avaxim™ given as booster doses 6 months later. Both vaccines elicited marked booster responses achieving antibody geometric mean titres (GMTs) of 4576 and 3760 mIU/ml in the HA/Vi and Avaxim™ groups, respectively. Although twice as frequent in the HA/Vi group, local reactions (mostly pain) were mainly mild and transient, probably reflecting the larger volume injected (1 ml). Vivaxim™ offers a convenient means of administering both HA and typhoid fever vaccines in subjects already primed for hepatitis A.     

Polio endgame: Lessons for the global rotavirus vaccination program

Poliovirus and rotavirus share notable similarities. Although rotavirus is not amenable to eradication because of animal reservoirs, live, attenuated oral vaccines have been the bedrock of both prevention and control programs, providing intestinal and humoral immunity. Both programs have also encountered safety concerns and suboptimal immune responses to oral vaccines in low-income settings that have been challenges, prompting the search for alternative solutions. In this paper, we review the progress made by polio prevention and eradication efforts over the past six decades. Specifically, we discuss the roles of the oral polio vaccine (OPV) and the inactivated polio vaccine (IPV) in achieving polio eradication, and explore potential application of these lessons to rotavirus. Recent scientific evidence has confirmed that a combined schedule of IPV and OPV adds synergistic value that may give the polio eradication effort the tools to end all poliovirus circulation worldwide. For rotavirus, oral vaccine is the only currently licensed and recommended vaccine for use in all children worldwide, providing heterologous protection against a broad range of strains. However, parenteral rotavirus vaccines are in the pre-clinical and clinical trial stage and insight from polio provides strong justification for accelerating the development of these vaccines. While challenges for parenteral rotavirus vaccines will need to be addressed, such as achieving protection against a broad range of strains, the principle of combined use of oral and parenteral rotavirus vaccines may provide the necessary humoral and intestinal immunity necessary to close the efficacy gaps between developing and developed countries, therefore controlling rotavirus worldwide. This strategy may also potentially reduce risk of intussusception.     

Poxvirus-vectored vaccines for rabies—A review

Oral rabies vaccination of target reservoir species has proved to be one of the pillars of successful rabies elimination programs. The use of live attenuated rabies virus vaccines has been extensive but several limitations hamper its future use. A recombinant vaccinia-rabies vaccine has also been successfully used for the oral vaccination of several species. Nevertheless, its lack of efficacy in certain important rabies reservoirs and concerns on the use of this potent live virus as vaccine carrier (vector) impair the expansion of its use for new target species and new areas. Several attenuated and host-restricted poxvirus alternatives, which supposedly offer enhanced safety, have been investigated. Once again, efficacy in certain target species and innocuity through the oral route remain major limitations of these vaccines. Alternative recombinant vaccines using adenovirus as an antigen delivery vector have been extensively investigated and may provide an important addition to the currently available oral rabies vaccine repertoire, but are not the primary subject of this review.     

Safety and immunogenicity of a Vi-DT typhoid conjugate vaccine: Phase I trial in Healthy Filipino adults and children

BackgroundTyphoid fever remains a major public health problem in low- and middle-income countries where children aged 2–14 years bear the greatest burden. Vi polysaccharide is poorly immunogenic in children <2 years of age, and protection in adults is modest. The limitations of Vi polysaccharide vaccines can be overcome by conjugation of the Vi to a carrier protein. A typhoid conjugate vaccine composed of Vi polysaccharide conjugated to diphtheria toxoid (Vi-DT) has been developed. The Phase I study results are presented here.MethodsThis was a randomized, observer-blinded Phase I study to assess the safety and immunogenicity of Vi-DT compared to Vi polysaccharide vaccine, conducted in Manila, Philippines. Participants enrolled in an age de-escalation manner (18–45, 6–17 and 2–5 years) were randomized between Test (Vi-DT, 25 µg) administered at 0 and 4 weeks and Comparator (Vi polysaccharide, Typhim Vi® and Vaxigrip®, Sanofi Pasteur) vaccines.ResultsA total of 144 participants were enrolled (48 by age strata, 24 in Test and Comparator groups each). No serious adverse event was reported in either group. Solicited and unsolicited adverse events were mild or moderate in both groups with the exception of a 4-year old girl in Test group with grade 3 fever which resolved without sequelae. All participants in Test group seroconverted after first and second doses of Vi-DT while the proportions in the Comparator group were 97.1% and 97.2%, after first dose of Typhim Vi® and second dose of Vaxigrip®, respectively. Vi-DT showed 4-fold higher Geometric Mean Titers (GMT) compared to Typhim Vi® (adjusted for age strata, p < 0.001). No further increase of GMT was detected after the second dose of Vi-DT. Anti-DT IgG seroresponse rates were 81.2% and 84.5% post first and second Vi-DT doses, respectively.ConclusionsVi-DT vaccine was safe, well-tolerated and immunogenic in participants aged 2–45 years.ClinicalTrials.gov registration number: NCT02645032.     

Animal models paving the way for clinical trials of attenuated Salmonella enterica serovar Typhi live oral vaccines and live vectors

Attenuated Salmonella enterica serovar Typhi (S. Typhi) strains can serve as safe and effective oral vaccines to prevent typhoid fever and as live vectors to deliver foreign antigens to the immune system, either by the bacteria expressing antigens through prokaryotic expression plasmids or by delivering foreign genes carried on eukaryotic expression systems (DNA vaccines). The practical utility of such live vector vaccines relies on achieving a proper balance between minimizing the vaccine's reactogenicity and maximizing its immunogenicity. To advance to clinical trials, vaccine candidates need to be pre-clinically evaluated in relevant animal models that attempt to predict what their safety and immunogenicity profile will be when administered to humans. Since S. Typhi is a human-restricted pathogen, a major obstacle that has impeded the progress of vaccine development has been the shortcomings of the animal models available to assess vaccine candidates. In this review, we summarize the usefulness of animal models in the assessment of the degree of attenuation and immunogenicity of novel attenuated S. Typhi strains as vaccine candidates for the prevention of typhoid fever and as live vectors in humans.