Controlled Human Infection Models To Accelerate Vaccine Development

Abstract

The timelines for developing vaccines against infectious diseases are lengthy, and often vaccines that reach the stage of large phase 3 field trials fail to provide the desired level of protective efficacy. The application of controlled human challenge models of infection and disease at the appropriate stages of development could accelerate development of candidate vaccines and, in fact, has done so successfully in some limited cases. Human challenge models could potentially be used to gather critical information on pathogenesis, inform strain selection for vaccines, explore cross-protective immunity, identify immune correlates of protection and mechanisms of protection induced by infection or evoked by candidate vaccines, guide decisions on appropriate trial endpoints, and evaluate vaccine efficacy. We prepared this report to motivate fellow scientists to exploit the potential capacity of controlled human challenge experiments to advance vaccine development. In this review, we considered available challenge models for 17 infectious diseases in the context of the public health importance of each disease, the diversity and pathogenesis of the causative organisms, the vaccine candidates under development, and each model's capacity to evaluate them and identify correlates of protective immunity. Our broad assessment indicated that human challenge models have not yet reached their full potential to support the development of vaccines against infectious diseases. On the basis of our review, however, we believe that describing an ideal challenge model is possible, as is further developing existing and future challenge models.

Keywords: controlled human infection model; human challenge model; vaccine.

FIG 1

Plasmodium life cycle and malaria challenge platforms.

FIG 2

Parasite strains and mosquito vectors commonly used in challenge models.

FIG 3

Preerythrocytic human challenge models using mosquito bite delivery or direct venous inoculation of infectious sporozoites.

FIG 4

Blood-stage controlled human malaria infection.

FIG 5

Transmission-stage challenge model.

FIG 6

Malaria vaccine development from controlled human malaria infection to the field and back.

FIG 7

Potential mechanisms for immune-mediated enhancement of dengue virus infection.

FIG 8

Diagram of influenza virus structural elements.

FIG 9

Structure of influenza hemagglutinin with a globular head domain (red) and elongated stalk domain (green).

FIG 10

Phylogenetic classification of human influenza A and B viruses according to the hemagglutinin gene.

FIG 11

Inactivated influenza A virus vaccine manufacture.

FIG 12

Range of current and new vaccine approaches against influenza A virus.

FIG 13

Structural diagram of respiratory syncytial virus.

FIG 14

Transmission and pathology of tuberculosis.

FIG 15

Distinct mechanisms of immunity induced with whole-cell and acellular pertussis vaccines.