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31 May 2024
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Controlled Human Infection Model's (CHIM) in your backpack: how Human Challenge Trials support regulatory approval of travellers vaccines

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Introduction

A ‘travellers vaccine’ is a vaccine administered to travellers from a ‘non-endemic region’, before they travel to an endemic region, and they form an important component of travel medicine. Beyond protection of travellers, they are also administered to prevent the importation of vaccine-preventable diseases ‘at home’. Proof of immunization to travel dates back to the first smallpox vaccine in 1796. It took another century to develop the next generation of vaccines against cholera, rabies, and typhoid fever. During the 20th century, the range of vaccines used by travellers largely expanded with yellow fever, poliomyelitis, tetravalent meningococcal, and hepatitis A vaccines. The International Certificate of Inoculation and Vaccination was implemented in 1933. 1

Currently, vaccines are administered to travellers following a risk assessment based on their destination and individual risk factors, but certain countries also mandate certain vaccines.

Most of the time, vaccines administered to travellers have been developed for use in endemic regions. In a number of cases, vaccines have been specifically developed to serve the travellers market. This blog will present a case study of how Human Challenge Trials can support the regulatory development of this type of vaccine.

Cholera  - Overview

Cholera is a severe, rapidly-dehydrating diarrheal disease caused by toxigenic serogroups of the bacterium Vibrio cholerae. It constituted the greatest epidemic disease of the 19th century.

Cholera is endemic in areas of Africa, the Indian sub-and Southeast Asia, where it remains a disease associated with poverty and poor sanitation, Recently cholera cases have been reported in the Caribbean (Haiti and Dominican Republic). In developed countries, cholera is extremely rare, and cases are traced to travellers returning from endemic areas. 2

Developing a cholera vaccine for travellers using a Controlled Human Infection Model

Vaxchora is a live oral cholera vaccine intended to prevent cholera disease in adults and children aged from 6 years (18 years in the US).

The vaccine is specifically aimed at travellers travelling to cholera-endemic regions. It contains a weakened form of the cholera bacterium Vibrio cholerae (serogroup O1). Vaxchora received marketing authorisation valid throughout the EU in April 2020 and was approved by the FDA in June 2016. 3,4

Developing a vaccine for cholera – in particular one aimed at travellers – has a major challenge as performing a Phase III field trial in this population would be difficult, as both the placebo and the active group would need to be meaningfully exposed to cholera – in the same order of magnitude – in order to achieve a conclusive result on efficacy. To be able to demonstrate efficacy, a Controlled Human Infection Model (CHIM) trial was included in the development pathway as the pivotal efficacy study, replacing a Phase III efficacy field trial. In this CHIM study, 197 healthy adults aged 18 to 45 years received a single dose of either Vaxchora (95 volunteers) or placebo (102 volunteers) and were then given infectious cholera bacteria (O1 strain).

The CHIM trial showed that Vaxchora can prevent symptoms of cholera in people coming into contact with the bacteria and provided the pivotal part of the efficacy data. In order to have a sufficiently large safety database, a main safety immunogenicity study involving 3,022 healthy adults aged 18 to 45 years was performed. Two further studies in special populations confirmed that giving Vaxchora to adults aged 46 to 64 years or to children and adolescents aged 6 to 18 years was effective at producing antibodies against cholera bacteria.

Conclusion

Human challenge trials do not only play a role in supporting the development of vaccines by serving as a proof-of-concept trial, but as the above example illustrates, can in some very specific cases, also be used as a more pivotal element of the development.

References

  1. Pavli A, Maltezou HC. Travel vaccines throughout history. Travel Med Infect Dis. 2022 Mar-Apr;46:102278..
  2.  Gabutti G., Rossanese A., Tomasi A., Giuffrida S., Nicosia V., Barriga J., et al. Cholera, the current status of cholera vaccines and recommendations for travellers. Vaccines. 2020;8:606.
  3. Vaxchora: EPAR EMA/82271/2020 Committee for Medicinal Products for Human Use (CHMP) assessment report. Vaxchora International non-proprietary name: cholera vaccine, oral, live Procedure No. EMEA/ H/C/003876/0000
  4. FDA. Vaxchora information

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