Zika virus (ZIKV) is a mosquito-borne flavivirus that has rapidly extended its geographic range around the world. Its association with abnormal fetal brain development, sexual transmission, and lack of a preventive vaccine have constituted a global health concern. Designing a safe and effective vaccine requires significant caution due to overlapping geographical distribution of ZIKV with dengue virus (DENV) and other flaviviruses, possibly resulting in more severe disease manifestations in flavivirus immune vaccinees such as Antibody-Dependent Enhancement (ADE, a phenomenon involved in pathogenesis of DENV, and a risk associated with ZIKV vaccines using the envelope proteins as immunogens). Here, we describe the development of an alternative vaccine strategy encompassing the expression of ZIKV non-structural-1 (NS1) protein from a clinically proven safe, Modified Vaccinia Ankara (MVA) vector, thus averting the potential risk of ADE associated with structural protein-based ZIKV vaccines. A single intramuscular immunization of immunocompetent mice with the MVA-ZIKV-NS1 vaccine candidate provided robust humoral and cellular responses, and afforded 100% protection against a lethal intracerebral dose of ZIKV (strain MR766). This is the first report of (i) a ZIKV vaccine based on the NS1 protein and (ii) single dose protection against ZIKV using an immunocompetent lethal mouse challenge model.

The goal of an HIV vaccine is to generate robust and durable protective antibody. Vital to this goal is the induction of CD4+ T follicular helper cells (TFH). However, very little is known about the TFH response to HIV vaccination and its relative contribution to magnitude and quality of vaccine-elicited antibody titers. Here, we investigated these questions in the context of a DNA/modified vaccinia virus Ankara (MVA) SIV vaccine with and without gp140 boost in alum in rhesus macaques. In addition, we determined the frequency of vaccine-induced CD4+ T cells co-expressing chemokine receptor, CXCR5 (facilitates migration to B cell follicles) in blood and whether these responses were representative of lymph node (LN) TFH responses. We show that booster MVA immunization induced a distinct and transient accumulation of proliferating CXCR5+ and CXCR5− CD4 T cells in blood at day 7-post immunization and the frequency of the former but not the latter correlated with TFH and B cell responses in germinal centers (GC) of LN. Interestingly, gp140 boost induced a skewing towards CXCR3 expression on GC TFH cells, which was strongly associated with longevity, avidity, and neutralization potential of vaccine-elicited antibody response. However, CXCR3+ cells preferentially expressed the HIV co-receptor CCR5 and vaccine-induced CXCR3+ CXCR5+ cells showed a moderate positive association with peak viremia following SIV251 infection. Taken together, our findings demonstrate that vaccine regimens that elicit CXCR3 biased TFH cell responses favor antibody persistence and avidity but may predispose to higher acute viremia in the event of breakthrough infections.

The inhibitory receptor Programmed Death-1 (PD-1) has been shown to regulate CD8 T cell function during chronic SIV infection, however its role on CD4 T cells, specifically in the gut associated lymphoid tissue, is less well understood. Here, we show that a subset of CD4 T cells express high levels of PD-1 (PD-1hi) in the rectal mucosa, a preferential site of virus replication. The majority of these PD-1hi CD4 T cells expressed Bcl-6 and CXCR5, markers characteristic of T follicular helper cells in the lymph nodes. Following a pathogenic SIV infection, the frequency of PD-1hi cells (as a percent of CD4 T cells) dramatically increased in the rectal mucosa, however a significant fraction of them did not express CXCR5. Furthermore, only a small fraction of PD-1hi cells expressed CCR5 and despite this low level of viral co-receptor expression a significant fraction of these cells were productively infected. Interestingly, vaccinated SIV controllers did not present with this aberrant PD-1hi CD4 T cell enrichment and this lack of enrichment was associated with the presence of higher frequencies of SIV-specific granzyme B+ CD8 T cells within the lymphoid tissue, suggesting a role for anti-viral CD8 T cells in limiting aberrant expansion of PD-1hi CD4 T cells. These results highlight the importance of developing vaccines that enhance anti-viral CD8 T cells at sites of preferential viral replication and support the need for developing therapeutic interventions that limit expansion of SIV+ PD-1hi CD4 T cells at mucosal sites as a means to enhance viral control.

Ebola virus (EBOV), isolate Makona, was the causative agent of the West African epidemic devastating predominantly Guinea, Liberia and Sierra Leone from 2013–2016. While several experimental vaccine and treatment approaches have been accelerated through human clinical trials, there is still no approved countermeasure available against this disease. Here, we report the construction and preclinical efficacy testing of a novel recombinant modified vaccinia Ankara (MVA)-based vaccine expressing the EBOV-Makona glycoprotein GP and matrix protein VP40 (MVA-EBOV). GP and VP40 form EBOV-like particles and elicit protective immune responses. In this study, we report 100% protection against lethal EBOV infection in guinea pigs after prime/boost vaccination with MVA-EBOV. Furthermore, this MVA-EBOV protected macaques from lethal disease after a single dose or prime/boost vaccination. The vaccine elicited a variety of antibody responses to both antigens, including neutralizing antibodies and antibodies with antibody-dependent cellular cytotoxic activity specific for GP. This is the first report that a replication-deficient MVA vector can confer full protection against lethal EBOV challenge after a single dose vaccination in macaques.

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