Typhoid Vaccine

Mechanism of Action

Unconjugated Typhoid Vaccines

Ty21a vaccine: The live attenuated Ty21a strain lacks uridine-diphosphate-galactose-4-epimerase, resulting in the inability to manufacture Vi polysaccharide and a cytoplasmic accumulation of galactose that eventually causes cell lysis.[7] This vaccine induces the production of serum and intestinal mucosal antibodies against O, H, and other surface antigens but not against the Vi polysaccharide. The strength of the initial response mediated by IgA antibody-secreting cells and the presence of anti-O IgG antibodies are the best markers of protection.[4] A long-lasting cell-mediated immunity develops and includes a specific cytotoxic T-lymphocyte response.

The Ty21a vaccine has a cumulative efficacy of 43% (CI 30%-53%; 4 trials) over 1 to 5 years of follow-up among participants aged 3 to 44.[1] The patient's age during vaccination does not affect this efficacy. Other oral vaccines, such as Rotarix, polio, and cholera, demonstrate poor efficacy in low and middle-income countries (LMIC) due to various factors, including higher rates of concomitant gastrointestinal disease, microbial dysbiosis, and mucosal tolerance.[1] The Ty21a vaccine may be more effective for the populations of high-income countries, but no evidence exists to support this. Maximum effectiveness requires taking all doses.

ViPS vaccine: Immunization initially induces increased production of IgG anti-Vi antibodies, which are found in elevated levels in the serum. The immune system develops an immunologic memory in response to ViPS vaccination, as polysaccharide antigens do not induce T-cell production. Antibody titer levels decline significantly by the third year after immunization.[4]

This vaccine has an estimated cumulative efficacy of 57% (CI 44%-69%; 5 trials) over 1 to 3 years among participants aged 2 to 50.[1] The patient's age is unlikely to affect vaccine efficacy, although insufficient power and a large margin of uncertainty of vaccine efficacy in children younger than 5 may obscure any significant differences.[4]

Typhoid Conjugate Vaccines

All TCVs contain 25 μg of Vi polysaccharide conjugated with a protein carrier. This carrier component engages B and T-cells, inducing germinal center development in the spleen and lymph nodes. Within germinal centers, polysaccharide-specific B-cells proliferate and differentiate through hypermutation of the antibody genes. Follicular helper T-cells aid this process once activated by the protein carrier presented by the major histocompatibility complex on the B-cell surface.[8] An increased affinity of the B-cell receptor antibody to the antigen increases the aid provided by T-cells via cytokines and direct cell-to-cell interaction. Repeated cycles produce higher-affinity antibodies and antibody class switching, similar to the immune response during a typical infection. B-cells in germinal centers that do not engage T-cells undergo apoptosis.[8]

Along with a 2024 systematic review and meta-analysis, new randomized controlled trials (RCTs) studying the efficacy of typhoid vaccines for preventing culture-confirmed S Typhi infection support the results reported in previous reviews, such as the 2018 Cochrane Review. These study data include newer conjugate vaccines and extended observation periods.[1][9][10] The systematic review found no RCTs studying typhoid vaccine efficacy in populations of nonendemic countries; all data are from studies in endemic countries.[1] RCTs studying the efficacy of conjugated vaccines are few but growing in number.

An update to the 2018 Cochrane Review of Typhoid Vaccines is pending; a protocol was registered with the Cochrane Library in March 2023.[26] This update will focus solely on TCVs. Human challenge and other immunogenicity studies provide additional evidence of vaccine efficacy, cited here for vaccines without efficacy data.

ViTT vaccines: The Vi-tetanus toxoid conjugate (Vi-TT) vaccine is conjugated with a nontoxic tetanus toxoid carrier.[26] Vi-TT is available in 2 formulations: Typbar-TCV^® and PedaTyph^TM (BioMed, India). A single dose of the Typbar-TCV^® Vi-TT vaccine has a cumulative efficacy of 83% (CI 77% to 88%; 4 trials) 1 to 2 years post-immunization in infants and children aged 6 months to 16 years.[1] The most recent Typbar-TCV^® Vi-TT vaccine trial analysis in Malawian children aged 9 months to 12 years showed an efficacy of 78.3% (CI 66.3% to 86.1%) 4 years after a single dose.[9] Differences in efficacy were nonsignificant across age groups.

In an outbreak setting, the Typbar-TCV^® Vi-TT vaccine demonstrated 95% effectiveness (93% to 96%) against culture-confirmed S Typhi in children aged 6 months to 10 years during a study conducted from February 21, 2018, to December 31, 2019, in Hyderabad, Pakistan.[11] Despite only moderate deployment, this vaccine curtailed the outbreak.

An alternate formulation of Vi-TT (PedaTyph^TM) is licensed and marketed only in India.[4] This vaccine can be administered to children 3 months or older.[26] The 2018 Cochrane review reported an efficacy of 94% (CI 0%-101%) based on a single study. The actual effect is uncertain due to a wide confidence interval and a lack of unclustering during statistical analysis of the study data.[12]

Vi-CMR₁₉₇ vaccine

TyphiBev^TM is a Vi-CMR₁₉₇ conjugate vaccine comprising a Vi protein attached to a mutant nontoxic diphtheria toxoid. Vi-CMR₁₉₇ is non-inferior to the Vi-TT vaccine and demonstrates a seroconversion rate of 99.0% (CI 97.1% to 97.6%) versus 99.3% (CI 97.6% to 99.9%) for Vi-TT based on a seroconversion threshold of 2 μg/mL.[13] Immunogenicity response rates were consistent across age ranges from 6 months to 54 years. The serum geometric mean titers (GMTs) of anti-Vi IgG antibodies induced by Vi-CMR₁₉₇ and Vi-TT were comparable overall and across age ranges.[13]

Vi-Diphtheria toxoid vaccine

SKYTyphoid^® is a Vi-diphtheria toxoid vaccine (Vi-DT). The Vi-DT seroconversion rate of 99.7% (97.5%, CI 98.0% to 100.0%) is non-inferior to Vi-TT vaccination (99.1%, CI 94.3% to 100.0%) in participants aged 6 months to 45 years during a phase 3 trial based on a seroconversion threshold of 0.14 μg/mL.[6] No differences were observed across age strata. The anti-Vi IgG GMTs showed no differences across age strata compared to Vi-TT. However, significant differences occurred in participants aged 6 to 24 months; this group had more adverse effects and a significantly lower mean GMT compared to Vi-TT (50.2 vs 73.4 IU/mL) at 24 months.[6] Further study is needed to elaborate on this finding.

Vi-rEPA vaccine

Vi-rEPA is an early TCV conjugated with a recombinant exoprotein A from Pseudomonas aeruginosa. The efficacy of Vi-rEPA is 89% (CI 77%-95%; 1 trial) for 4 years post-administration of 2 vaccine doses.[1] Relevant studies did not include children younger than 2.[12] This vaccine is not commercially available.

Administration

Unconjugated Vaccines

Ty21a: Vaccination requires 4 oral enteric-coated capsules, each taken 48 hours apart. Each capsule is taken 1 hour before or at least 2 hours after a meal with water cooler than body temperature (≤37.0 °C). The capsules must be refrigerated until use. The patient must complete this series at least 1 week before a potential exposure.[25]

ViPS: Vaccination requires a single 0.5 mL (25 μg) intramuscular dose at least 2 weeks before a potential exposure.[25]

Typhoid Conjugate Vaccines

All TCVs require a single intramuscular dose, except for the PedaTyph^TM and Vi-rEPA vaccines, which require a 2-dose primary series separated over 4 to 8 weeks.[4] The optimal booster schedules for most TCVs remain undefined and depend on factors such as the vaccination age and the degree of natural boosting in the individual patient.[4][14] The manufacturer recommends an initial PedaTyph^TM immunization for infants aged 3 to 23 months, a booster at 24 to 30 months, and boosters every 10 years afterward.[26]

Coadministration with other vaccines

The Ty21a and ViPS vaccines can be administered with other travel or childhood vaccines, including live ones. Likewise, TCVs can be administered safely with other childhood vaccines, as demonstrated by the Malawi and Burkina Faso studies. Specifically, measles-rubella vaccines are safe and effective when administered at 9 and 15 months, yellow fever vaccine at 9 months, and meningococcal vaccine at 15 months.[14] Several recent and ongoing TCV study protocols require the concurrent administration of the study vaccine and routine childhood vaccines.[12]

Adverse Effects

Typhoid vaccines currently in use are safe and generally well tolerated. They may cause mild local or systemic adverse effects. However, study data shows these effects are similar to those caused by placebo or comparator vaccines used in trials (meningococcal, hepatitis, pneumococcal, or other TCV). Multiple studies report no serious adverse events associated with TCVs to date.[12][10][1][15][6][13] 

Each vaccine is associated with specific adverse effects:

• The oral Ty21a vaccine is commonly associated with fever compared to placebo.[12] Vomiting, diarrhea, nausea, and abdominal pain occur with similar frequency as with placebo.
• ViPS is commonly associated with injection site swelling and pain compared to placebo.[12]
• Vi-rEPA is associated with increased rates of fever after each vaccine dose. Swelling at the injection site was more common after the second dose compared to placebo.[12]

Contraindications

Pregnant and Lactating Women

Safety data for typhoid vaccine administration to pregnant and lactating women is lacking for all vaccines. The ViPS vaccine and TCVs are thought to have minimal or absent risk.[4] These can be safely administered if indicated.[16][4]

Live vaccines are not recommended during pregnancy due to theoretical risks to the pregnant woman or fetus.[4] The CDC recommends against administering Ty21a to pregnant women and avoiding conception until 4 weeks after immunization.[25]

Concurrent Conditions or Medications

The CDC recommends the ViPS vaccine for patients who are immunocompromised.[25] The ViPS vaccine and TCVs may be safely administered to patients who are immunocompromised, including those with HIV. However, an immunocompromised patient may demonstrate reduced production of protective antibodies following non-live typhoid vaccinations. This phenomenon is pronounced in patients who are severely immunocompromised due to conditions (eg, symptomatic HIV/AIDS, chronic lymphocytic leukemia, hematopoietic stem cell transplant, generalized cancer) or receiving immunosuppressive medications (eg, alkylating agents, antimetabolites, biologic agents. In patients with HIV, antibody induction with ViPS and TCVs correlates directly to the CD4⁺ count.[25]

The CDC also recommends against administering the live Ty21a vaccine to individuals with a known suppression of cell-mediated immunity, who have been receiving high-dose steroid therapy for 2 weeks or longer, or who are receiving chemotherapeutic or radiation therapy.[25] The WHO considers Ty21a safe to administer to patients with HIV and a CD4⁺ count of 200 cells/mm³ or greater (CD4⁺ >25% in children younger than 5).[4]

The immunogenicity of TY21a may be reduced in patients with acute severe gastrointestinal conditions; immunization for these patients should be delayed until after recovery. Other minor illnesses are not contraindications for these vaccines, although some individuals choose to delay vaccination until after recovery. Antibiotics may reduce immunogenicity, and concurrent administration with the Ty21a vaccine should be avoided. Various monoclonal antibodies may also interfere with antibody production.

An allergic reaction to any vaccine (or any of its components) is a contraindication for that vaccine.

Monitoring

No monitoring or routine testing is necessary with any of the vaccines described.

Toxicity

There is no toxicity associated with any typhoid vaccination formulation in the literature.

Enhancing Healthcare Team Outcomes

Understanding the rationale for using various typhoid vaccines is critical to providing optimal care to people at risk of typhoid infection in endemic and nonendemic countries. Knowledge of the presentation of enteric fever, diagnostic and treatment challenges, the rise of antimicrobial resistance, and implementation considerations aid healthcare providers in making healthcare recommendations regarding vaccination. This knowledge is also necessary to improve the implementation of vaccination programs and widespread prevent enteric illness.

Presentation and Diagnosis

Practitioners must advise healthy patients living in or traveling to endemic countries of the risk of S Typhi infection, its associated risk factors, early signs and symptoms, and when and how to seek help should they become ill. Practitioners must also monitor for early signs and symptoms of the disease in patients with typhoid fever to avoid complications and possible death.

Salmonella enterica serotype Typhi is a pathogen found only in humans. S Typhi is ingested through contaminated food or water, particularly in areas with inadequate WASH infrastructure. The bacteria can withstand stomach acid and penetrate the small bowel's epithelial enterocytes or lymphoid tissue. S Typhi is primarily spread by intracellular lymphatic and hematogenous routes. During typhoid challenge studies, patients develop a complex immune response to multiple bacterial antigens; those who become clinically ill do not develop antibodies to the Vi capsular polysaccharide of S Typhi.[17] The closely related Salmonella enterica serotypes Paratyphi A, B, and C (S Paratyphi) cause an illness clinically indistinguishable from Salmonella Typhi infection.[3]

Typhoid and paratyphoid fever are collectively referred to as enteric fever. In endemic areas, enteric fever is frequently confused with other nonspecific febrile illnesses. Following an incubation period of 6 to 30 days, enteric fever initially presents as an undifferentiated, progressive fever that increases with bacteremia. Fatigue, anorexia, headache, malaise, and abdominal symptoms are commonly accompanying symptoms. A faint macular rash on the trunk and abdomen ("rose spots") and hepatosplenomegaly may also occur.

Enteric fever can have severe outcomes, including death. Complications usually arise during the third week of illness; ileocecal perforation, peritonitis, or septic shock occur in 30% of patients who do not receive treatment.[18] Patients may have a protracted recovery lasting weeks or months. The bacteria may be present in the stool for months after infection. Five percent of patients become carriers and excrete S Typhi in the stool for over a year. Relapse of fever occurs in about 10% of untreated patients. Death occurs in 10% to 30% of patients who remain untreated.[18]

Culture from blood, stool, urine, bone marrow, duodenal contents, or skin rash is the gold standard for typhoid fever confirmation. However, blood culture (the most common laboratory testing) has low sensitivity (50% to 66%) for patients in endemic areas and is frequently unavailable in these regions. The sensitivity of blood culture testing is significantly greater (>90%) for travelers.[19] Newer rapid diagnostic tests are becoming increasingly available.

Treatment and Antimicrobial Resistance

The rapid development of S Typhi drug resistance worldwide makes antibiotic therapy challenging.[20] The WHO recommends initial treatment pending culture for patients with suspected enteric fever. Treatment varies between areas with and without known resistance to ciprofloxacin medications. Treatment is a third-generation cephalosporin for severe illness in all areas and a fluoroquinolone antibiotic or azithromycin for milder illness, depending on where the infection was acquired.[27] Knowing the sensitivity pattern for the area where the infection occurred guides initial antibiotic therapy.[21][22] A lack of access to affordable healthcare in many endemic countries, difficulties in diagnosis due to undifferentiated illness, poor diagnostic tools, and potentially severe outcomes contribute to the need for empiric therapy.[14]

The high rates of infection in many endemic countries and the use of empiric treatment place evolutionary pressure on the development of antimicrobial resistance, posing a significant global health threat. S Typhi acquires resistance genes from or transmits genes to other Salmonella species and other microbes. Multidrug-resistant (XDR) strains demonstrate resistance to ampicillin, trimethoprim-sulfamethoxazole, and chloramphenicol. The emergence of XDR typhoid in Pakistan in 2016 and its spread to at least 16 other countries is an alarming public health issue.[18] XDR strains also resist third-generation cephalosporins, leaving azithromycin and meropenem as the only effective antibiotics.[14][27][14]

Implementation

Highly effective vaccines are vital in preventing typhoid disease and the development of antimicrobial resistance globally. The first whole-cell typhoid vaccines emerged during the late 19th century but were associated with a high rate of severe side effects. Safe and effective unconjugated vaccines replaced these in the 1990s. However, unconjugated vaccines confer insufficient immunity to effectively prevent illness and outbreaks in endemic countries. The need for multiple doses and a limited age range for administering the Ty21a vaccine further limits the usefulness of this vaccine type in the most affected populations.

TCVs are changing the landscape of typhoid prevention and are now one of many routine childhood vaccines in highly endemic countries. They are also used to quell typhoid outbreaks. For example, TCV was effective in limiting an XDR outbreak in Pakistan in 2018 and 2019 that affected 14,984 people. Due to their importance in preventing XDR typhoid, TCVs are on the WHO list of essential medicines for priority diseases.[1]

Nonendemic countries

In nonendemic countries, including the United States, healthcare workers who provide primary care and vaccines to, or are in contact with, travelers must be aware of the increased risk of enteric and other illnesses. These travelers should also be informed of the increased risk of enteric infection if they visit certain regions. Nurse practitioners, primary care physicians, and pharmacists should direct patients to local health units or other practitioners who provide travel advice. Healthcare practitioners administering the vaccine should understand the indications, contraindications, and proper administration.

Travelers from nonendemic countries must understand that the typhoid vaccine prevents approximately 50% to 66% of typhoid fever infections. Immunization against S Typhi does not prevent paratyphoid fever or other gastrointestinal illnesses and does not preclude the need for food and water safety precautions, amongst other health measures. Frequent hand-washing and avoiding the local water supply and certain foods are critical.

Endemic countries

Collaboration between physicians, nurses, pharmacists, public and community health workers, and civil society partners is essential to implement typhoid vaccine programs effectively. Accurate assessments of typhoid epidemiology and other critical health issues, funding and secure vaccine supply, community trust building, safe transport, storage and administration of vaccines, and follow-up for adverse events are necessary for optimal program implementation. All TCVs require strict cold chain maintenance.

The WHO gives the highest priority for TCV use to highly endemic countries and those with high rates of XDR typhoid.[4] TCVs are preferred by the WHO to prevent typhoid fever due to their immunological properties, efficacy in young children, and prolonged duration of immunity compared to unconjugated vaccines.[4] Previously, only Typbar-TCV^® was WHO-prequalified, raising supply concerns. Since then, Vi-CMR₁₉₇^TM and SKYTyphoid^TM have become prequalified. A stable and cost-effective vaccine supply requires multiple vaccine types and manufacturers; several newer vaccines are at various stages of development.[14] The Vi-rEPA vaccine is not currently commercially available.

As of June 2024, 6 countries have incorporated TCV into their routine immunization schedules in combination with WASH interventions.[23] Several other countries are currently in the application or implementation process. Distribution is handled by international agencies such as the internationally-funded Gavi Global Vaccine Alliance.[23]

In addition to S Typhi vaccination, effective prevention of enteric fever requires a separate vaccine to prevent S Paratyphi. While the Ty21 vaccine demonstrates some cross-reactivity for Salmonella Paratyphi B, it does not confer sufficient immunity to be used clinically for S Paratyphi B prevention and is not FDA-approved for this purpose.[25] Improved diagnostic tools, water, sanitation, and hygiene infrastructure are essential to eliminate enteric fever as a global health threat. 

Other Prevention Measures 

Preventing typhoid fever and other enteric illnesses requires safe food and water practices and infrastructure. For travelers and people living in risk areas, washing hands before eating, eating foods thoroughly cooked and served hot, and eating personally peeled fruits are essential safeguards. Drinking water should be boiled, chemically disinfected, or bottled and personally opened.

Adequate WASH infrastructure is vital to decrease the incidence of typhoid fever in endemic countries. Developing an S Paratyphi vaccine is critical in the global fight against enteric fever and antimicrobial resistance, particularly in countries where S Paratyphi comprises a large part of the enteric fever burden.