Contribution of influenza immunity and virosomal-formulated synthetic peptide to cellular immune responses in a phase I subunit malaria vaccine trial

ABSTRACT Results from clinical trials in areas where malaria is endemic have shown that immunization with RTS,S/AS02A malaria vaccine candidate induces partial protection in adults and children and cellular effector and memory responses in adults. For the first time in a malaria vaccine trial, we sought to assess the cell-mediated immune responses to RTS,S antigen components in infants under 1 year of age participating in a clinical phase I/IIb trial of RTS,S/AS02D in Mozambique. Circumsporozoite protein (CSP)-specific responses were detected in approximately half of RTS,S-immunized infants and included gamma interferon (IFN-γ), interleukin-2 (IL-2), and combined IL-2/IL-4 responses. The median stimulation indices of cytokine-producing CD4+ and CD8+ cells were very low but significantly higher in RTS,S-immunized infants than in infants that received the comparator vaccine. Protection against subsequent malarial infection tended to be associated with a higher percentage of individuals with CSP-specific IL-2 in the supernatant (P = 0.053) and with higher CSP-specific IFN-γ-producing CD8+ T-cell responses (P = 0.07). These results report for the first time the detection of malaria-specific cellular immune responses after vaccination of infants less than 1 year of age and pave the way for future field studies of cellular immunity to malaria vaccine candidates.

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Liver-Directed AAV8 Booster Vaccine Expressing Plasmodium falciparum Antigen Following Adenovirus Vaccine Priming Elicits Sterile Protection in a Murine Model

Frontiers in Immunology ◽

10.3389/fimmu.2021.612910 ◽

2021 ◽

Vol 12 ◽

Author(s):

Mohammad Shahnaij ◽

Mitsuhiro Iyori ◽

Hiroaki Mizukami ◽

Mayu Kajino ◽

Iroha Yamagoshi ◽

...

Keyword(s):

T Cells ◽

Immune Responses ◽

Malaria Vaccine ◽

Infected Mosquito ◽

Great Promise ◽

Adeno Associated Virus ◽

Boost Regimen ◽

Cellular Immune Responses ◽

Virus Serotype ◽

Cellular Immune

Hepatocyte infection by malaria sporozoites is a bottleneck in the life-cycle of Plasmodium spp. including P. falciparum, which causes the most lethal form of malaria. Therefore, developing an effective vaccine capable of inducing the strong humoral and cellular immune responses necessary to block the pre-erythrocytic stage has potential to overcome the spatiotemporal hindrances pertaining to parasite biology and hepatic microanatomy. We recently showed that when combined with a human adenovirus type 5 (AdHu5)-priming vaccine, adeno-associated virus serotype 1 (AAV1) is a potent booster malaria vaccine vector capable of inducing strong and long-lasting protective immune responses in a rodent malaria model. Here, we evaluated the protective efficacy of a hepatotropic virus, adeno-associated virus serotype 8 (AAV8), as a booster vector because it can deliver a transgene potently and rapidly to the liver, the organ malaria sporozoites initially infect and multiply in following sporozoite injection by the bite of an infected mosquito. We first generated an AAV8-vectored vaccine expressing P. falciparum circumsporozoite protein (PfCSP). Intravenous (i.v.) administration of AAV8-PfCSP to mice initially primed with AdHu5-PfCSP resulted in a hepatocyte transduction rate ~2.5 times above that seen with intramuscular (i.m.) administration. This immunization regimen provided a better protection rate (100% sterile protection) than that of the i.m. AdHu5-prime/i.m. AAV8-boost regimen (60%, p < 0.05), i.m. AdHu5-prime/i.v. AAV1-boost (78%), or i.m. AdHu5-prime/i.m. AAV1-boost (80%) against challenge with transgenic PfCSP-expressing P. berghei sporozoites. Compared with the i.m. AdHu5-prime/i.v. AAV1-boost regimen, three other regimens induced higher levels of PfCSP-specific humoral immune responses. Importantly, a single i.v. dose of AAV8-PfCSP recruited CD8+ T cells, especially resident memory CD8+ T cells, in the liver. These data suggest that boost with i.v. AAV8-PfCSP can improve humoral and cellular immune responses in BALB/c mice. Therefore, this regimen holds great promise as a next-generation platform for the development of an effective malaria vaccine.

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Impact of Preexisting and Induced Humoral and Cellular Immune Responses in an Adenovirus-Based Gene Therapy Phase I Clinical Trial for Localized Mesothelioma

Human Gene Therapy ◽

10.1089/hum.1998.9.14-2121 ◽

1998 ◽

Vol 9 (14) ◽

pp. 2121-2133 ◽

Cited By ~ 154

Author(s):

Katherine L. Molnar-Kimber ◽

Daniel H. Sterman ◽

Michael Chang ◽

Eugen H. Kang ◽

Mohammed ElBash ◽

...

Keyword(s):

Clinical Trial ◽

Gene Therapy ◽

Immune Responses ◽

Phase I ◽

Phase I Clinical Trial ◽

Cellular Immune Responses ◽

Cellular Immune

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Phase I Clinical Study for Validation of Fimaporfin-Based Photochemical Internalisation: A Novel Technology for Enhancing Cellular Immune Responses Important for Therapeutic Effect of Peptide-and Protein-Based Vaccines

Annals of Oncology ◽

10.1093/annonc/mdz451.018 ◽

2019 ◽

Vol 30 ◽

pp. xi40-xi41 ◽

Cited By ~ 2

Author(s):

P.K. Selbo ◽

S. Janetzki ◽

M.J.P. Welters ◽

M. Håkerud ◽

A.G. Nedberg ◽

...

Keyword(s):

Clinical Study ◽

Immune Responses ◽

Phase I ◽

Therapeutic Effect ◽

Cellular Immune Responses ◽

Novel Technology ◽

Cellular Immune

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Synthetic peptide vaccination in cattle: induction of strong cellular immune responses against peptides derived from the Mycobacterium bovis antigen Rv3019c

Vaccine ◽

10.1016/j.vaccine.2005.04.022 ◽

2005 ◽

Vol 23 (35) ◽

pp. 4375-4384 ◽

Cited By ~ 15

Author(s):

H. Martin Vordermeier ◽

Reno Pontarollo ◽

Brenda Karvonen ◽

Paul Cockle ◽

Rolf Hecker ◽

...

Keyword(s):

Immune Responses ◽

Mycobacterium Bovis ◽

Synthetic Peptide ◽

Peptide Vaccination ◽

Cellular Immune Responses ◽

Cellular Immune

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Correction: Quantitative PCR Evaluation of Cellular Immune Responses in Kenyan Children Vaccinated with a Candidate Malaria Vaccine

PLoS ONE ◽

10.1371/annotation/9a1d1873-2f7e-4d69-a1b0-8e3797e8093a ◽

2011 ◽

Vol 6 (2) ◽

Author(s):

Jedidah Mwacharo ◽

Susanna J. Dunachie ◽

Oscar Kai ◽

Adrian V. S. Hill ◽

Philip Bejon ◽

...

Keyword(s):

Immune Responses ◽

Quantitative Pcr ◽

Malaria Vaccine ◽

Cellular Immune Responses ◽

Candidate Malaria Vaccine ◽

Cellular Immune

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Towards the spanish vaccine against SARS-CoV-2, responsible for the pandemic Covid-19

ANALES RANM ◽

10.32440/ar.2020.137.02.rev18 ◽

2020 ◽

Vol 137 (137(02)) ◽

pp. 234-238

Author(s):

Mariano Esteban ◽

Juan García Arriaza

Keyword(s):

Clinical Trials ◽

Immune Responses ◽

Phase I ◽

Neutralizing Antibodies ◽

Cultured Cells ◽

Wide Spectrum ◽

Cellular Immune Responses ◽

Cellular Immune ◽

Vaccinia Virus Strain

There is a general consensus that the only way to stop the pandemic caused by the coronavirus SARS-CoV-2 is through the development of an effective and safe vaccine. Various countries have move forward to develop a vaccine, and currently a number of preclinical and clinical trials phase I/II revealed that some of the vaccines triggered activation of humoral and cellular immune responses that could be relevant in protection against the coronavirus, but it remains yet to demonstrated efficacy in the population of any of the vaccines. Our group of Poxvirus and Vaccines at the CNB-CSIC started with the development of a vaccine immediately after the full genome (30.000 nucleotides) sequence of the SARS-CoV-2 was published in January 10, 2020. In this article we describe the steps that we have follow up to develop a vaccine candidate using as a vector (vehicle) an attenuated strain of modified vaccinia virus strain (MVA) expressing the full-length S (Spike) protein of SARS-CoV-2. We have demonstrated in cultured cells and in animals (mice) that the vaccine fulfills relevant criteria to be considered a candidate against COVID-19, like expression of the entire protein at the cell membrane, formation of oligomers (trimers), high stability and ability to induce neutralizing antibodies, a type of Th1 response and induction of a wide spectrum of SARS-CoV-2 specific T cells, like CD4+, CD8+, Tfh, Tregs and memory cells. We have programmed efficacy studies in animals (humanized mice and macaques) and phase I/II and III clinical trials. The GMP lot is under production by an Spanish company and a patent has been presented.

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