Adjuvant-enhanced CD4 T Cell Responses are Critical to Durable Vaccine Immunity

Martins, Karen; Cooper, Christopher L.; Stronsky, Sabrina M.; Norris, Sarah L.; Kwilas, Steven A.; Steffens, Jesse; Benko, Jacqueline G.; Tongeren, Sean A. Van; Bavari, Sina

doi:10.1016/j.ebiom.2015.11.041

Cited by 54 publications

(58 citation statements)

References 88 publications

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“…As the magnitude of the T cell response is dependent on its ability to expand in response to antigen, this assay reflects an important feature of vaccine-induced CMI (28-30). The (38); P ϭ 0.0177 b a A responder was defined as a subject with an antigen-stimulated response that was Ն2ϫ higher than that seen with the respective negative (no stimulation) control and was Ն0.02% after subtraction of the respective negative (no stimulation) control data. Where indicated, P values represent results from Fisher's exact tests comparing the number of responders to the number seen under the same stimulation conditions between day 0 and day 56; NS, not significant.…”

Section: Discussionmentioning

confidence: 99%

Cell-Mediated Immunity Generated in Response to a Purified Inactivated Vaccine for Dengue Virus Type 1

Friberg

Martínez

Lin

et al. 2020

mSphere

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Dengue is the most prevalent arboviral disease afflicting humans, and a vaccine appears to be the most rational means of control. Dengue vaccine development is in a critical phase, with the first vaccine licensed in some countries where dengue is endemic but demonstrating insufficient efficacy in immunologically naive populations. Since virus-neutralizing antibodies do not invariably correlate with vaccine efficacy, other markers that may predict protection, including cell-mediated immunity, are urgently needed. Previously, the Walter Reed Army Institute of Research developed a monovalent purified inactivated virus (PIV) vaccine candidate against dengue virus serotype 1 (DENV-1) adjuvanted with alum. The PIV vaccine was safe and immunogenic in a phase I dose escalation trial in healthy, flavivirus-naive adults in the United States. From that trial, peripheral blood mononuclear cells obtained at various time points pre- and postvaccination were used to measure DENV-1-specific T cell responses. After vaccination, a predominant CD4+ T cell-mediated response to peptide pools covering the DENV-1 structural proteins was observed. Over half (13/20) of the subjects produced interleukin-2 (IL-2) in response to DENV peptides, and the majority (17/20) demonstrated peptide-specific CD4+ T cell proliferation. In addition, analysis of postvaccination cell culture supernatants demonstrated an increased rate of production of cytokines, including gamma interferon (IFN-γ), IL-5, and granulocyte-macrophage colony-stimulating factor (GM-CSF). Overall, the vaccine was found to have elicited DENV-specific CD4+ T cell responses as measured by enzyme-linked immunosorbent spot (ELISpot), intracellular cytokine staining (ICS), lymphocyte proliferation, and cytokine production assays. Thus, together with antibody readouts, the use of a multifaceted measurement of cell-mediated immune responses after vaccination is a useful strategy for more comprehensively characterizing immunity generated by dengue vaccines. IMPORTANCE Dengue is a tropical disease transmitted by mosquitoes, and nearly half of the world’s population lives in areas where individuals are at risk of infection. Several vaccines for dengue are in development, including one which was recently licensed in several countries, although its utility is limited to people who have already been infected with one of the four dengue viruses. One major hurdle to understanding whether a dengue vaccine will work for everyone—before exposure—is the necessity of knowing which marker can be measured in the blood to signal that the individual has protective immunity. This report describes an approach measuring multiple different parts of immunity in order to characterize which signals one candidate vaccine imparted to a small number of human volunteers. This approach was designed to be able to be applied to any dengue vaccine study so that the data can be compared and used to inform future vaccine design and/or optimization strategies.

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Section: Discussionmentioning

confidence: 99%

Cell-Mediated Immunity Generated in Response to a Purified Inactivated Vaccine for Dengue Virus Type 1

Friberg

Martínez

Lin

et al. 2020

mSphere

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“…The first study, by Martins et al, was related to an Ebola-VLP vaccine with which mice had great short-term protection against Ebola challenge but lost protection over time (88). Testing a series of different adjuvants to increase long-term durable immunity showed that only poly(IC) was effective at inducing long-term immunity.…”

Section: Novel Translational and Clinical Research Strategies To Provmentioning

confidence: 99%

Waning Immunity and Microbial Vaccines—Workshop of the National Institute of Allergy and Infectious Diseases

Plotkin

Edwards

et al. 2017

Clin Vaccine Immunol

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Since the middle of the 20th century, vaccines have made a significant public health impact by controlling infectious diseases globally. Although long-term protection has been achieved with some vaccines, immunity wanes over time with others, resulting in outbreaks or epidemics of infectious diseases. Long-term protection against infectious agents that have a complex life cycle and antigenic variation remains a key challenge. Novel strategies to characterize the short-and long-term immune responses to vaccines and to induce immune responses that mimic natural infection have recently emerged. New technologies and approaches in vaccinology, such as adjuvants, delivery systems, and antigen formulations, have the potential to elicit more durable protection and fewer adverse reactions; together with in vitro systems, these technologies have the capacity to model and accelerate vaccine development. The National Institute of Allergy and Infectious Diseases (NIAID) held a workshop on 19 September 2016 that focused on waning immunity to selected vaccines (for Bordetella pertussis, Salmonella enterica serovar Typhi, Neisseria meningitidis, influenza, mumps, and malaria), with an emphasis on identifying knowledge gaps, future research needs, and how this information can inform development of more effective vaccines for infectious diseases.

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“…27 Protein-based vaccines are relatively less immunogenic because the potency of T-cell activation is low. 36 Thus, the ssRNA adjuvants must compensate for these deficiencies. The gE protein produced from the CHO-K1 cell expression system-induced VZV gE-specific antibody.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of glycoprotein E subunit and live attenuated varicella‐zoster virus vaccines formulated with a single‐strand RNA‐based adjuvant

Lee

Park

et al. 2020

Immunity Inflam & Disease

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Introduction: Varicella-zoster virus (VZV), a human alphaherpesvirus 3, elicits both chickenpox and shingles and/or postherpetic neuralgia. A live attenuated vaccine (LAV) and glycoprotein E (gE) subunit vaccine were developed to prevent VZV-induced diseases. We recently reported that single-strand RNA (ssRNA) based on the intergenic region of the internal ribosome entry site of cricket paralysis virus (CrPV) is an effective adjuvant for protein-based and virus-like particle-based vaccines. Here, Chinese hamster ovary expression system and an LAV from Oka/SK strains. Methods: We appraised the adjuvant effect of the same CrPV ssRNA encoding the gE gene formulated in the two vaccines using VZV-primed C57BL/6 mice and guinea pigs. Humoral immunity and cell-mediated immunity were assessed by enzyme-linked immunosorbent assay (ELISA) and ELISPOT in gE subunit vaccine and by ELISA and fluorescent antibody to membrane antigen in LAV. Results: The gE subunit vaccine-induced gE-specific antibodies and CD4 + T-cell responses (indicated by interferon-γ [IFN-γ] and interleukin-2 secretion) in the ssRNA-based adjuvant containing the VZV gE gene. Therefore, an ssRNA adjuvant combined with gE antigen can trigger the innate immune response and induce an adaptive immune response to ultimately activate humoral and cell-mediated responses. VZV LAV could also induce VZV-specific antibodies and IFN-γ stimulated by LAV, whereas the effect of ssRNA as a ---This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. contributed equally to this study.vaccine adjuvant could not be confirmed. However, the ssRNA adjuvant increased VZV-specific neutralizing antibody response. Conclusions: Taken together, these results highlight that the gE subunit vaccine and LAV developed in this study can be functional VZV vaccines, and ssRNAs appear to function better as adjuvants in a subunit vaccine than in an LAV. K E Y W O R D S chickenpox, gE subunit vaccine, live attenuated vaccine, RNA adjuvant, shingles, varicella-zoster virus

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Adjuvant-enhanced CD4 T Cell Responses are Critical to Durable Vaccine Immunity

Cited by 54 publications

References 88 publications

Cell-Mediated Immunity Generated in Response to a Purified Inactivated Vaccine for Dengue Virus Type 1

Cell-Mediated Immunity Generated in Response to a Purified Inactivated Vaccine for Dengue Virus Type 1

Waning Immunity and Microbial Vaccines—Workshop of the National Institute of Allergy and Infectious Diseases

Evaluation of glycoprotein E subunit and live attenuated varicella‐zoster virus vaccines formulated with a single‐strand RNA‐based adjuvant

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