Development of Vi conjugate – a new generation of typhoid vaccine

Abstract

Typhoid fever remains to be a serious disease burden worldwide with an estimated annual incidence about 20 million. The licensed vaccines showed moderate protections and have multiple deficiencies. Most important of all, none of the licensed typhoid vaccines demonstrated protection for children under 5 years old. These limitations impeded successful implementation of typhoid vaccination programs. To improve immunogenicity Vi was conjugated to rEPA, a recombinant exoprotein A from Pseudomonas aeruginosa. Vi-rEPA showed higher and longer lasting anti-Vi IgG in adults and children than Vi alone in high endemic areas. In school-age children and adults, the immunity persisted more than 8 years. In a double-blind, placebo-controlled and randomized efficacy trial in 2- to 5-year-old children, Vi-rEPA conferred 89% protective efficacy against typhoid fever and the protection lasted at least 4 years. When given concomitantly with infant routine vaccines, Vi-rEPA was safe, immunogenic and showed no interference with the routine vaccines. Vi conjugate vaccine was also attempted and successfully demonstrated by several other laboratories and manufactures. Using either rEPA or different carrier proteins, such as diphtheria or tetanus toxoid, recombinant diphtheria toxin (CRM₁₉₇), the Vi conjugates synthesized was significantly more immunogenic than Vi alone. Recently, two Vi-tetanus toxoid conjugates were licensed in India for all ages, starts as young as 3 month old. This new generation of typhoid vaccine opens up a new era for typhoid prevention and elimination.

Keywords::

• infants
• typhoid fever
• vaccine development
• Vi conjugate
• young children

Acknowledgements

The author would like to thank the typhoid conjugate study team at the NIH and typhoid conjugate clinical study teams at Cao Lanh District, Dong Tho Province, Pasteur Institute in Hochiming City, Phu Tho Province, and National Institute of Epidemiology and Hygiene in Vietnam. Contributions and comments to this study represent the author’s own best judgment and do not bind or obligate organizations listed above.

Financial & competing interests disclosure

This research was supported by the Intramural Research Program of the NIH, Eunice Kennedy Shriver National Institute of Child Health and Human Development. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• • Typhoid fever remains a health problem worldwide. Safe, effective and affordable typhoid vaccines are currently available. The new generation of Vi conjugate vaccine conferred higher and longer protection against typhoid fever than the current vaccines.

• • Single injection of Vi conjugate in school-age children and adults provided >8 years protection, eliminates the need for multiple dose regimens or re-injection every 3 years.

• • Efficacy trial showed Vi conjugate protects pre-school age children between 2 and 5 years old with 90% efficacy for 4 years.

• • Vi-rEPA demonstrated to be safe and immunogenic when given concomitantly with routine vaccines to infants and can be incorporated into the Expanded Program of Immunization.

• • Among various method of Vi conjugate synthesis, adipic dihydrazide scheme showed to be simple, reproducible and was successfully adopted by most of the manufactures in the field.

• • Clinical trials of Vi conjugates made with various clinical relevant toxoids consistently reaffirmed the safety and demonstrated superiority over the licensed Vi polysaccharide vaccine.

• • Key physicochemical and serological markers are compiled based on existing clinical studies. It can be helpful to establish product profile for new Vi conjugates and allows new product to surrogate with existing clinical data for potency evaluation [101].

• • Giving the success of the investigational vaccine Vi-rEPA, in order for Vi conjugate to advance into production level, there are still many questions unanswered, such as: the ideal dosage, formulation, stability, cold chain requirement or improvement, optimum number of injections and immunization schedule, especially for children under 2 years old.

• • Currently, there exists an estimated protective level of anti-Vi IgG. This value appears to be too conservative. A closer study to derive a more realistic protective level is incumbent.

• • Consideration should be given to include Vi conjugate in combination form with other vaccines. An ideal vaccine to control enteric fever would be a combination vaccine composed of Vi conjugate and non-typhoidal conjugates that are still under development.

• • During the past decade, global non-profit organizations including the Bill Melinda Gates Foundation, Sabin Vaccine Institute and International Vaccine Institute, joint forces with local public health organizations build up comprehensive strategies for typhoid control, including integrated vaccination program along with supply of clean water and sanitation improvement. The participation of the new generation Vi conjugate vaccine will accelerate the process of typhoid elimination [102–104].