GACVS previously reviewed the safety of typhoid vaccines, including the newer generation of typhoid conjugate vaccines (TCVs), in December 2016.³ The Committee noted that its conclusions and recommendations formed part of the evidence reviewed by the Strategic Advisory Group of Experts (SAGE) on immunization for a revised policy and an updated WHO position paper on the use of typhoid vaccines, issued in March 2018.⁴ The new position paper includes the first recommendation for routine use of TCV as a single intramuscular dose for primary vaccination of infants and children from 6 months of age and adults ≤45 years of age and in catch-up campaigns in children ≤15 years of age in typhoid-endemic regions. Further, TCV is recommended for the control of typhoid in epidemic settings.

GACVS received newly available data on the Vi-tetanus toxoid conjugate vaccine Typbar-TCVTM (produced by Bharat Biotech International Limited), currently the only licensed TCV available internationally and prequalified by WHO. The data comprised preliminary safety data on Typbar-TCVTM from three ongoing trials of effectiveness in the field conducted by the Typhoid Vaccine Acceleration Consortium (TyVAC), data from early public sector use of the vaccine in India and Pakistan and data from private sector use in India reported to the manufacturer.

The Committee reviewed the preliminary results of individually randomized control trials by the TyVAC in Malawi and Nepal (with Group A meningococcal vaccine as the control) and a cluster randomized trial in Bangladesh (with Japanese encephalitis SA14-14-2 vaccine as the control). While only blinded data could be presented to GACVS, they represent adverse events data from approximately 24 000 children and SAE data for approximately 99 000 children aged between 9 months and 15 years in the TCV and control arms in the 3 trial sites. Solicited local and systemic adverse reactions were reported with a similar frequency in the 2 arms at all trial sites, and most events were of mild or moderate severity. Specifically, fever and pain were reported in 3–8% and 1–7% of vaccinees in each arm, respectively, while other non-specific local and systemic reactions occurred in 0–3% of vaccinees in each arm. The occurrence of serious adverse events was similar in the 2 arms.

Additional data were presented on passive and active surveillance of adverse events in 2 mass immunization campaigns with TCV in 2018: (i) in response to a typhoid outbreak caused by an extensively drug-resistant strain of Salmonella Typhi in Hyderabad, Pakistan; and (ii) for introduction of the vaccine into the routine childhood immunization programme in Navi Mumbai, India. Approximately 110 000 doses of TCV were administered in each campaign to children aged 6 months to 10 years in Pakistan and aged 9 months to less than 15 years in India. Preliminary results from the 2 campaigns showed an adverse event profile similar to those of other routine injectable vaccines, with low rates of mild-to-moderate local and systemic events overall. Fever, pain and swelling at the injection site were the commonest adverse events in both settings. Data from passive surveillance suggested underreporting of adverse events; however, active surveillance was robust, as supported by the use of Brighton Collaboration case definitions. At 5 sentinel hospital sites in Navi Mumbai, 43 cases of thrombocytopenia were observed among vaccine recipients, and 299 cases were observed among unvaccinated children (no statistically significant difference between the 2 groups). The large number of thrombocytopenia cases among unvaccinated children and a final diagnosis of dengue reported in more than half the cases suggested ongoing transmission of dengue viral infection unrelated to the TCV campaign.

Post-licensure safety data for Typbar-TCVTM reported to the manufacturer (with approximately 8 million doses marketed), based on approximately 9000 reports received from paediatricians in the private sector in India and through periodic safety reports, showed an acceptable safety profile (similar to that in public sector use) and did not raise any safety signals.

On the basis of the available data from a variety of settings, GACVS concluded that the safety profile of the Typbar-TCVTM vaccine is reassuring, and no signals of serious adverse events were presented. The Committee also noted the absence of prior theoretical safety concerns for this TCV in the safety profile of its components. Nonetheless, GACVS recommends that countries that introduce TCV into their routine immunization schedule or into campaigns make every effort to ensure robust monitoring of safety (as for any new vaccine) in order to add data on co-administration of TCV with other routine childhood vaccines or in special populations, to detect any signals that require further investigation and to maintain public confidence in the immunization programme.

Further analysis of unblinded safety data from the ongoing TyVAC trials and from the campaigns in Pakistan and India, including the safety profile of TCV in malnourished children, are expected and will be considered by the Committee when they become available. GACVS will also consider future reviews of safety data as warranted, in particular for special populations, including pregnant women. It recommends examination of concomitant administration with other vaccines, such as that against measles, mumps and rubella (MMR), in large-scale campaigns with the currently available TCV and with additional TCVs with different carrier proteins, which are in development.

³ See No. 92, 2017, pp. 17–19.

⁴ See No. 93, 2018, pp. 153–172.

Full report of GACVS meeting of 5-6 December 2018, published in the WHO Weekly Epidemiological Record on 25 January 2019

GACVS was presented with data on the safety of 3 generations of typhoid vaccines, including the live oral Ty21a vaccine, parenteral Vi polysaccharide, and conjugated Vi polysaccharide vaccines. The Ty21a and Vi polysaccharide vaccines are currently recommended by WHO for programmatic use to control endemic and epidemic disease,⁶ while a review by SAGE for recommendations on the conjugate vaccines is scheduled for 2017.

Ty21a (currently only available as enteric-coated capsules) is recommended in individuals aged ≥5 years in a 3-dose (most countries) or a 4-dose regimen (in Canada and the United States); it confers protection in 62% of vaccinees for up to 7 years. The Vi polysaccharide vaccine is recommended for use as a single dose in individuals aged ≥2 years and confers protection in the range of ~55–65% for 2–3 years. Overall, Ty21a and the Vi polysaccharide vaccines are estimated to have been used in several million and several hundred thousand doses respectively over 3 decades. Both vaccines have a good safety profile, with the most common adverse events being fever (both vaccines), erythema and localized pain, and gastrointestinal events (primarily with Ty21a). Other adverse events are generally rare.

The first Vi conjugated vaccine (based on Vi antigen conjugated to a recombinant exoprotein A from Pseudomonas aeruginosa, (Vi-rEPA)) was evaluated in randomized control trials of >11 000 subjects in Viet Nam, and had a safety profile similar to that of the polysaccharide vaccine.^7,8 This vaccine was not commercialized. However, 2 other conjugated Vi polysaccharide vaccines (with tetanus toxoid as the carrier protein) have been licensed by the national regulatory authority in India.

One product, the Pedatyph vaccine produced by Bio-Med Limited has been evaluated for safety in approximately 2200 subjects (immunogenicity was evaluated in 400 subjects in pre-licensure trials, while effectiveness was evaluated in 1765 subjects in a Phase IV trial). In the available published data, no safety signals have been reported and the most frequent adverse events described are local, non-specific reactions and fever.

More detailed data were presented for Typbar-TCV vaccine (produced by Bharat Biotech International Limited) which has been evaluated for immunogenicity and safety in approximately 1000 subjects pre-licensure.⁹ By the time of the meeting, more than 3 million doses of this conjugate vaccine had been distributed in the private sector. Post-licensure, the vaccine has been evaluated in a study of co-administration with measles containing vaccines (MCV), and in a Phase IV comparator study with the pre-qualified Vi polysaccharide vaccine (with a total of 470 vaccine recipients in the 2 studies). In these pre- and post-licensure studies, the adverse event profile was similar to the specific comparator vaccines in respective age groups; no safety signals were reported. However, safety follow-up was largely passive and data available limited. Data from the co-administration study (of 500 infants in 3 arms receiving Typbar-TCV alone, MCV alone, or both vaccines) showed no demonstrable interference with the immune response to either the Typbar-TCV or MCV. Post-marketing surveillance data, based on approximately 3000 reports received from pediatricians in the private sector in India, showed fever, pain and swelling were reported in approximately 1–10% of vaccinees in any age group; no serious adverse events were reported to the manufacturer. However, the overall reporting rate in this study was low and did not identify serious coincidental events that would have been expected. Based on the data presented, GACVS did not identify any new signals of serious adverse events with any of the existing typhoid vaccines. With regard to the licensed Vi-tetanus toxoid conjugate vaccines, while the safety profile appeared similar to the Vi polysaccharide vaccine, limited safety data were generated.

The Committee reviewed post-marketing safety data for one of the Vi-TT conjugate vaccines and noted limitations to the available data. It therefore recommended conducting further safety monitoring of typhoid conjugate vaccines with the following considerations: i) the need for a stronger post-marketing surveillance was highlighted, particularly in view of the lack of reported coincidental illnesses anticipated in the vaccinated age groups; ii) with large effectiveness studies of conjugate vaccine being planned, it is important that their design ensures robust safety evaluation including any potential safety risks in special population groups (e.g. malnourished children, immunocompromised individuals and, where applicable, pregnant women); iii) further safety evaluations should use the Brighton Collaboration case definitions and actively monitor serious adverse events of interest; iv) where feasible, non-specific effects of vaccination should be analysed.

⁶ See N°. 6, 2008, pp. 49–60.

⁷ Lin FYC, Ho VA, Khiem HB, Trach DD, Bay PV et al. The efficacy of a Salmonella Typhi Vi conjugate vaccine in two-to-five-year-old children. N Engl J Med 2001;344:1263–1269.

⁸ Thiem VD, Lin FYC, Canh DG, Son NH, Anh DD et al. The Vi conjugate typhoid vaccine is safe, elicits protective levels of IgG anti-Vi, and is compatible with routine infant vaccines. Clin. Vaccine Immunol 2011;18:730–735.

⁹ Mohan VK, Varanasi V, Singh A, Pasetti M Levine MM et al. Safety and Immunogenicity of a Vi Polysaccharide–Tetanus Toxoid Conjugate Vaccine (Typbar-TCV) in Healthy Infants, Children, and Adults in Typhoid Endemic Areas: A Multicenter, 2-Cohort, Open-Label, Double-Blind, Randomized Controlled Phase 3 Study. Clin Infect Dis. 2015;61:393–402.

Full report of GACVS meeting of 30 November-1 December 2016, published in the WHO Weekly Epidemiological Record on 13 January 2017