Controlled Human Malaria Infection (CHMI) differentially affects cell-mediated and antibody responses to CSP and AMA1 induced by adenovirus vaccines with and without DNA-priming

Abstract

We have previously shown that a DNA-prime followed by an adenovirus-5 boost vaccine containing CSP and AMA1 (DNA/Ad) successfully protected 4 of 15 subjects to controlled human malaria infection (CHMI). However, the adenovirus-5 vaccine alone (AdCA) failed to induce protection despite eliciting cellular responses that were often higher than those induced by DNA/Ad. Here we determined the effect of CHMI on pre-CHMI cellular and antibody responses against CSP and AMA1 expressed as fold-changes in activities. Generally, in the DNA/Ad trial, CHMI caused pre-CHMI ELISpot IFN-γ and CD8+ T cell IFN-γ responses of the protected subjects to fall but among non-protected subjects, CHMI caused rises of pre-CHMI ELISpot IFN-γ but falls of CD8+ T cell IFN-γ responses. In contrast in the AdCA trial, CHMI caused both pre-CHMI ELISpot IFN-γ and CD8+ T cell IFN-γ responses of the AdCA subjects to fall. We suggest that the falls in activities are due to migration of peripheral CD8+ T cells to the liver in response to developing liver stage parasites, and this fall, in the DNA/Ad trial, is masked in ELISpot responses of the non-protected subjects by rises in other immune cell types. In addition, CHMI caused falls in antibody activities of protected subjects, but rises in non-protected subjects in both trials to CSP, and dramatically in the AdCA trial to AMA1, reaching 380 μg/ml that is probably due to boosting by transient blood stage infection before chloroquine treatment. Taken together, these results further define differences in cellular responses between DNA/Ad and AdCA trials, and suggest that natural transmission may boost responses induced by these malaria vaccines especially when protection is not achieved.

Keywords:

• antibody
• adenovirus-boost
• AMA1
• CSP
• CHMI
• DNA -prime
• efficacy
• malaria
• T cells
• vaccine

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Acknowledgments

The authors thank all the study volunteers who participated in the trial. We thank Dr. Thomas L. Richie, former Director of the NMRC Malaria Department, and Dr. Carter Diggs and Dr. Lorraine Soisson of the US Agency for International Development (USAID) for their involvement in the design of the clinical trials used in this study. Active duty military personnel at the time they contributed to this work: CT, IC, and JEE. MS and EV were US Government employees. The work of these individuals was prepared as part of official government duties. Title 17 USC. §105 provides that “Copyright protection under this title is not available for any work of the United States Government.” Title 17 USC. §101 defines a US Government work as a work prepared by a military service member or employee of the US Government as part of that person's official duties. The study protocol for the clinical trial presented in this manuscript was approved by the WRAIR and NMRC Institutional Review Boards, in compliance with all applicable Federal Regulations governing protection of human subjects. All volunteers gave written informed consent. The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Department of the Navy, the Department of the Army, the Department of Defense, or the US Government.

Funding

This work was supported by USAID “Development of Adenovirus-Vectored Malaria Vaccines” Grant # GHA-P-00-03-00006-01, Project Number 936–3118; and the Congressionally Directed Medical Research Program “Development of Recombinant Adenoviral-based Vaccines against Malaria” Grant # W81XWH- 05-2-0041. Website https://cdmrp.org; Military Infectious Research Program “Phase 1/2a clinical trials assessing the safety, tolerability, immunogenicity and protective efficacy of Ad5-CA, a 2-antigen, adenovirus-vectored Plasmodium falciparum malaria vaccine, in healthy, malaria-naive adults work unit number 62787A 870 F 1432. The funders reviewed and approved the study design. The funders had no role in the data collection and analysis, or decision to prepare and publish this manuscript.

Trial Registrations

DNA/Ad: ClinicalTrials.gov NCT00870987; AdCA: NCT00392015