Novel ELISA method as exploratory tool to assess immunity induced by radiated attenuated sporozoites to decipher protective immunity

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Abstract

Background

Whole parasite vaccines provide a unique opportunity for dissecting immune mechanisms and identify antigens that are targeted by immune responses which have the potential to mediate sterile protection against malaria infections. The radiation attenuated sporozoite (PfSPZ) vaccine has been considered the gold standard for malaria vaccines because of its unparalleled efficacy. The immunogenicity of this and other vaccines continues to be evaluated by using recombinant proteins or peptides of known sporozoite antigens. This approach, however, has significant limitations by relying solely on a limited number of known pathogen-associated immune epitopes. Using the full range of antigens expressed by the sporozoite will enable the comprehensive immune-profiling of humoral immune responses induced by whole parasite vaccines. To address this challenge, a novel ELISA based on sporozoites was developed.

Results

The SPZ-ELISA method described in this report can be performed with either freshly dissected sporozoites or with cryopreserved sporozoite lysates. The use of a fixative for reproducible coating is not required. The SPZ-ELISA was first validated using monoclonal antibodies specific for CSP and TRAP and then used for the characterization of immune sera from radiation attenuated sporozoite vaccinees.

Conclusion

Applying this simple and highly reproducible approach to assess immune responses induced by malaria vaccines, both recombinant and whole parasite vaccines, (1) will help in the evaluation of immune responses induced by antigenically complex malaria vaccines such as the irradiated SPZ-vaccine, (2) will facilitate and accelerate the identification of immune correlates of protection, and (3) can also be a valuable assessment tool for antigen discovery as well as down-selection of vaccine formulations and, thereby, guide vaccine design.

Electronic supplementary material

The online version of this article (10.1186/s12936-017-2129-9) contains supplementary material, which is available to authorized users.

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Most cited references 16

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Live attenuated malaria vaccine designed to protect through hepatic CD8⁺ T cell immunity.

J. E. Epstein, K. Tewari, K Lyke … (2011)

Our goal is to develop a vaccine that sustainably prevents Plasmodium falciparum (Pf) malaria in ≥80% of recipients. Pf sporozoites (PfSPZ) administered by mosquito bites are the only immunogens shown to induce such protection in humans. Such protection is thought to be mediated by CD8(+) T cells in the liver that secrete interferon-γ (IFN-γ). We report that purified irradiated PfSPZ administered to 80 volunteers by needle inoculation in the skin was safe, but suboptimally immunogenic and protective. Animal studies demonstrated that intravenous immunization was critical for inducing a high frequency of PfSPZ-specific CD8(+), IFN-γ-producing T cells in the liver (nonhuman primates, mice) and conferring protection (mice). Our results suggest that intravenous administration of this vaccine will lead to the prevention of infection with Pf malaria.

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Sterile protection against human malaria by chemoattenuated PfSPZ vaccine

Benjamin Mordmüller, Guzin Surat, Heimo Lagler … (2017)

A highly protective malaria vaccine would greatly facilitate the prevention and elimination of malaria and containment of drug-resistant parasites. A high level (more than 90%) of protection against malaria in humans has previously been achieved only by immunization with radiation-attenuated Plasmodium falciparum (Pf) sporozoites (PfSPZ) inoculated by mosquitoes; by intravenous injection of aseptic, purified, radiation-attenuated, cryopreserved PfSPZ (‘PfSPZ Vaccine’); or by infectious PfSPZ inoculated by mosquitoes to volunteers taking chloroquine or mefloquine (chemoprophylaxis with sporozoites). We assessed immunization by direct venous inoculation of aseptic, purified, cryopreserved, non-irradiated PfSPZ (‘PfSPZ Challenge’) to malaria-naive, healthy adult volunteers taking chloroquine for antimalarial chemoprophylaxis (vaccine approach denoted as PfSPZ-CVac). Three doses of 5.12 × 104 PfSPZ of PfSPZ Challenge at 28-day intervals were well tolerated and safe, and prevented infection in 9 out of 9 (100%) volunteers who underwent controlled human malaria infection ten weeks after the last dose (group III). Protective efficacy was dependent on dose and regimen. Immunization with 3.2 × 103 (group I) or 1.28 × 104 (group II) PfSPZ protected 3 out of 9 (33%) or 6 out of 9 (67%) volunteers, respectively. Three doses of 5.12 × 104 PfSPZ at five-day intervals protected 5 out of 8 (63%) volunteers. The frequency of Pf-specific polyfunctional CD4 memory T cells was associated with protection. On a 7,455 peptide Pf proteome array, immune sera from at least 5 out of 9 group III vaccinees recognized each of 22 proteins. PfSPZ-CVac is a highly efficacious vaccine candidate; when we are able to optimize the immunization regimen (dose, interval between doses, and drug partner), this vaccine could be used for combination mass drug administration and a mass vaccination program approach to eliminate malaria from geographically defined areas.

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Gamma interferon, CD8+ T cells and antibodies required for immunity to malaria sporozoites.

L. Schofield, J Villaquiran, A. Ferreira … (1987)

This study was designed to test the hypothesis that T-cell effector mechanisms are required for protective immunity to malaria sporozoites. Administration of neutralizing monoclonal antibodies against gamma interferon (gamma IFN) to immune hosts, reversed sterile immunity to sporozoite challenge, by allowing the growth of exoerythrocytic forms (EEF) and thus the development of parasitaemia. Immune animals also developed infections when depleted in vivo of their suppressor/cytotoxic T cells expressing the CD8 antigen (CD8+) but not when depleted of helper T cells expressing CD4 antigen (CD4+), before sporozoite challenge. Passive transfer of immune immunoglobin alone, or adoptive transfer of immune T cells alone, conferred partial protection to naive recipients. Transfer of both immune components resulted in significantly greater protection. This transferred immunity was reversed by the in vivo neutralization of gamma IFN. Thus, sterile immunity to sporozoite challenge requires the neutralization of sporozoites by antibodies and the inhibition of EEF development by gamma IFN with the participation of CD8+ cells.

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Author and article information

Contributors

Trey A. Knepper: tknep001@odu.edu

Elizabeth H. Duncan: elizabeth.h.duncan2.ctr@mail.mil

Tatyana Savransky: tatyana.savransky.ctr@mail.mil

Elke S. Bergmann-Leitner:

ORCID: http://orcid.org/0000-0002-8571-8956

301-319-9278 , elke.s.bergmann-leitner.civ@mail.mil

Journal

Journal ID (nlm-ta): Malar J

Journal ID (iso-abbrev): Malar. J

Title: Malaria Journal

Publisher: BioMed Central (London )

ISSN (Electronic): 1475-2875

Publication date (Electronic): 29 November 2017

Publication date PMC-release: 29 November 2017

Publication date Collection: 2017

Volume: 16

Electronic Location Identifier: 484

Affiliations

[1 ]Malaria Vaccine Branch, U.S. Military Malaria Research Program, 503 Robert Grant Ave, 3W53, Silver Spring, MD 20910 USA

[2 ]ISNI 0000 0001 0036 4726, GRID grid.420210.5, Division of Entomology, , Walter Reed Army Institute of Research Walter Reed Army Institute of Research, ; 503 Robert Grant Ave, 3W53, Silver Spring, MD 20910 USA

Author information

Elke S. Bergmann-Leitner http://orcid.org/0000-0002-8571-8956

Article

Publisher ID: 2129

DOI: 10.1186/s12936-017-2129-9

PMC ID: 5707923

PubMed ID: 29187199

SO-VID: 543eea8e-669c-4f64-96c6-22de2346d54d

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 11 September 2017

Date accepted : 18 November 2017

Funding

Funded by: Military Infectious Disease Research Program

Award ID: F0410_14_WR_CS_OC

Award Recipient : Elke S. Bergmann-Leitner

Custom metadata

ScienceOpen disciplines: Infectious disease & Microbiology

Keywords: malaria,immunity,correlates of protection,plasmodium,assay development,sporozoite,antibodies

Data availability:

ScienceOpen disciplines: Infectious disease & Microbiology

Keywords: malaria, immunity, correlates of protection, plasmodium, assay development, sporozoite, antibodies

Novel ELISA method as exploratory tool to assess immunity induced by radiated attenuated sporozoites to decipher protective immunity

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Abstract

Background

Results

Conclusion

Electronic supplementary material

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Malaria vaccine development

Most cited references 16

Live attenuated malaria vaccine designed to protect through hepatic CD8⁺ T cell immunity.

Sterile protection against human malaria by chemoattenuated PfSPZ vaccine

Gamma interferon, CD8+ T cells and antibodies required for immunity to malaria sporozoites.

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