Dengue vaccine–induced CD8+ T cell immunity confers protection in the context of enhancing, interfering maternal antibodies

Lam, Jian Hang; Chua, Yen Leong; Lee, Pei Xuan; Gómez, Julia María Martínez; Ooi, Eng Eong; Alonso, Sylvie

doi:10.1172/jci.insight.94500

Cited by 33 publications

(38 citation statements)

References 82 publications

(105 reference statements)

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“…Importantly, we demonstrated that JEV-elicited CD8 + T cells protected against ZIKV infection even in the presence of pathogenic levels of JEVimmune Abs. These findings are in line with studies demonstrating that DENV-elicited CD8 + T cells protect against ADE induced by an inactivated DENV vaccine in adult mice (Zellweger et al, 2014) and against ADE induced by maternal Abs in infant mice (Lam et al, 2017). Taken together, these observations suggest that interplay between the Ab and CD8 + T cell responses to primary flavivirus infection dictates the outcome of a secondary heterologous flavivirus infection, and they additionally emphasize the key role of cross-reactive CD8 + T cell responses in mediating protective immunity in this setting.…”

Section: Discussionsupporting

confidence: 90%

Japanese encephalitis virus–primed CD8+ T cells prevent antibody-dependent enhancement of Zika virus pathogenesis

Dong

Duan

Zhou

et al. 2020

Journal of Experimental Medicine

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Cross-reactive anti-flaviviral immunity can influence the outcome of infections with heterologous flaviviruses. However, it is unclear how the interplay between cross-reactive antibodies and T cells tilts the balance toward pathogenesis versus protection during secondary Zika virus (ZIKV) and Japanese encephalitis virus (JEV) infections. We show that sera and IgG from JEV-vaccinated humans and JEV-inoculated mice cross-reacted with ZIKV, exacerbated lethal ZIKV infection upon transfer to mice, and promoted viral replication and mortality upon ZIKV infection of the neonates born to immune mothers. In contrast, transfer of CD8+ T cells from JEV-exposed mice was protective, reducing the viral burden and mortality of ZIKV-infected mice and abrogating the lethal effects of antibody-mediated enhancement of ZIKV infection in mice. Conversely, cross-reactive anti-ZIKV antibodies or CD8+ T cells displayed the same pathogenic or protective effects upon JEV infection, with the exception that maternally acquired anti-ZIKV antibodies had no effect on JEV infection of the neonates. These results provide clues for developing safe anti-JEV/ZIKV vaccines.

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Section: Discussionsupporting

confidence: 90%

Japanese encephalitis virus–primed CD8+ T cells prevent antibody-dependent enhancement of Zika virus pathogenesis

Dong

Duan

Zhou

et al. 2020

Journal of Experimental Medicine

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“…It is worth noting that no CMI studies were performed in that study and that the role of CMI in the dengue nonhuman primate model in general is unclear. CD8 ϩ T cell-mediated protection has been demonstrated in mouse models of DENV infection (53)(54)(55)(56), and correlative evidence in humans also supports a likely protective role for CD8 ϩ T cells, or for functional subsets thereof (27,57). The lack of CD8 ϩ T cell responses induced by the PIV-1 vaccine, while such responses are anticipated given its antigenic nature, may therefore be cause for concern.…”

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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“…However, the precise immune correlates of protection are yet to be elucidated 46 . Though nAbs are regarded as mediators of protection against flaviviral infections, in the case of DENVs, it appears that both humoral 43 as well as cellular 47 immunity may contribute to protection. Moreover, it is also recognised that incomplete or partial immunisation could carry the risk of serious dengue in the future 48 .…”

Section: Discussionmentioning

confidence: 99%

Dengue envelope-based ‘four-in-one’ virus-like particles produced using Pichia pastoris induce enhancement-lacking, domain III-directed tetravalent neutralising antibodies in mice

Rajpoot

Shukla

Arora

et al. 2018

Sci Rep

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Dengue is a significant public health problem worldwide, caused by four antigenically distinct mosquito-borne dengue virus (DENV) serotypes. Antibodies to any given DENV serotype which can afford protection against that serotype tend to enhance infection by other DENV serotypes, by a phenomenon termed antibody-dependent enhancement (ADE). Antibodies to the viral pre-membrane (prM) protein have been implicated in ADE. We show that co-expression of the envelope protein of all four DENV serotypes, in the yeast Pichia pastoris, leads to their co-assembly, in the absence of prM, into tetravalent mosaic VLPs (T-mVLPs), which retain the serotype-specific antigenic integrity and immunogenicity of all four types of their monomeric precursors. Following a three-dose immunisation schedule, the T-mVLPs elicited EDIII-directed antibodies in mice which could neutralise all four DENV serotypes. Importantly, anti-T-mVLP antibodies did not augment sub-lethal DENV-2 infection of dengue-sensitive AG129 mice, based on multiple parameters. The ‘four-in-one’ tetravalent T-mVLPs possess multiple desirable features which may potentially contribute to safety (non-viral, prM-lacking and ADE potential-lacking), immunogenicity (induction of virus-neutralising antibodies), and low cost (single tetravalent immunogen produced using P. pastoris, an expression system known for its high productivity using simple inexpensive media). These results strongly warrant further exploration of this vaccine candidate.

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Dengue vaccine–induced CD8+ T cell immunity confers protection in the context of enhancing, interfering maternal antibodies

Cited by 33 publications

References 82 publications

Japanese encephalitis virus–primed CD8+ T cells prevent antibody-dependent enhancement of Zika virus pathogenesis

Japanese encephalitis virus–primed CD8+ T cells prevent antibody-dependent enhancement of Zika virus pathogenesis

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

Dengue envelope-based ‘four-in-one’ virus-like particles produced using Pichia pastoris induce enhancement-lacking, domain III-directed tetravalent neutralising antibodies in mice

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