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The programmed cell death 1 (PD-1) pathway represents a major immune checkpoint which may be engaged by cells in a tumor microenvironment to overcome active T-cell immune surveillance. Pembrolizumab (Keytruda®) is a potent and highly selective humanized monoclonal antibody (mAb) of the IgG4/κ isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2. The current work was focused on developing a mouse T-Dependent Antibody Response (TDAR) model using a murinized rat anti-mouse PD-1 antibody (muDX400; a rodent surrogate for pembrolizumab) to evaluate the potential impact of treatment with a PD-1 inhibitor on immune responses to an antigen challenge (e.g. HBsAg in Hepatitis B vaccine). Despite the lower binding affinity and T1/2 compared to pembrolizumab, ligand blocking data indicated muDX400 had appropriate pharmacological activity and demonstrated efficacy in mouse tumor models, thus was suitable for pharmacodynamic and vaccination studies in mice. In a vaccination study in which mice were concomitantly administered muDX400 and the Hepatitis B vaccine, muDX400 was well-tolerated and did not result in any immune-mediated adverse effects. The treatment with muDX400 was associated with a shift in the ratio between naive and memory cells in both CD4+ and CD8+ T-lymphocytes in the spleen but did not affect anti-HBsAg antibody response profile. The mouse TDAR model using the Hepatitis B vaccine and the surrogate anti-PD1 monoclonal antibody was a useful tool in the evaluation of the potential immune-mediated effects of pembrolizumab following vaccination and appears to be a suitable alternative for the nonhuman primate TDAR models utilized for other checkpoint inhibitors. [ABSTRACT FROM AUTHOR]

The article discusses a study on the use of a replication-defective human cytomegalovirus vaccine to prevent congenital infection. The study examined a vaccine candidate with genetic modifications to improve its immunogenicity and attenuation. It used a synthetic compound named Shield-1 to regulate viral replication. The results revealed that the vaccine induced neutralizing antibodies to multiple viral antigens.

ZOSTAVAX® is a live attenuated varicella-zoster virus (VZV) vaccine that is licensed for the protection of individuals ≥50 years against shingles and its most common complication, postherpetic neuralgia. While IFNγ responses increase upon vaccination, the quality of the T cell response has not been elucidated. By using polychromatic flow cytometry, we characterized the breadth, magnitude, and quality of ex vivo CD4+ and CD8+ T cell responses induced 3-4 weeks after ZOSTAVAX vaccination of healthy adults. We show, for the first time that the highest frequencies of VZV-specific CD4+ T cells were poly-functional CD154+IFNγ+IL-2+TNFα+ cells, which were boosted upon vaccination. The CD4+ T cells were broadly reactive to several VZV proteins, with immediate early (IE) 63 ranking the highest among them in the fold rise of poly-functional cells, followed by IE62, gB, open reading frame (ORF) 9, and gE. We identified a novel poly-functional ORF9-specific CD8+ T cell population in 62% of the subjects, and these were boosted upon vaccination. Poly-functional CD4+ and CD8+ T cells produced significantly higher levels of IFNγ, IL-2, and TNFα compared to mono-functional cells. After vaccination, a boost in the expression of IFNγ by poly-functional IE63- and ORF9-specific CD4+ T cells and IFNγ, IL-2, and TNFα by ORF9-specific poly-functional CD8+ T cells was observed. Responding poly-functional T cells exhibited both effector (CCR7-CD45RA-CD45RO+), and central (CCR7+CD45RA-CD45RO+) memory phenotypes, which expressed com- parable levels of cytokines. Altogether, our studies demonstrate that a boost in memory poly-functional CD4+ T cells and ORF9-specific CD8+ T cells may contribute toward ZOSTAVAX efficacy. [ABSTRACT FROM AUTHOR]

Background: Adenoviral (Ad) vaccine vectors represent both a vehicle to present a novel antigen to the immune system as well as restimulation of immune responses against the Ad vector itself. To what degree Ad-specific CD8+ T cells are restimulated by Ad vector vaccination is unclear, although such knowledge would be important as vector-specific CD8+ T cell expansion could potentially further limit Ad vaccine efficacy beyond Ad-specific neutralizing antibody alone. Methodology/Principal Findings: Here we addressed this issue by measuring human Adenovirus serotype 5 (Ad5)-specific CD8+ T cells in recipients of the Merck Ad5 HIV-1 vaccine vector before, during, and after vaccination by multicolor flow cytometry. Ad5-specific CD8+ T-cells were detectable in 95% of subjects prior to vaccination, and displayed primarily an effector-type functional profile and phenotype. Peripheral blood Ad5-specific CD8+ T-cell numbers expanded after Ad5-HIV vaccination in all subjects, but differential expansion kinetics were noted in some baseline Ad5-neutralizing antibody (Ad5 nAb) seronegative subjects compared to baseline Ad5 nAb seropositive subjects. However, in neither group did vaccination alter polyfunctionality, mucosal targeting marker expression, or memory phenotype of Ad5-specific CD8+ T-cells. Conclusions: These data indicate that repeat Ad5-vector administration in humans expands Ad5-specific CD8+ T-cells without overtly affecting their functional capacity or phenotypic properties. This is a secondary analysis of samples collected during the 016 trial. Results of the Merck 016 trial safety and immunogenicity have been previously published in the journal of clinical infectious diseases. [ABSTRACT FROM AUTHOR]

The immunologic basis for the potential enhanced HIV-1 acquisition in adenovirus serotype 5 (Ad5)-seropositive individuals who received the Merck recombinant Ad5 HIV-1 vaccine in the STEP study remains unclear. Here we show that baseline Ad5-specific neutralizing antibodies are not correlated with Ad5-specific T lymphocyte responses and that Ad5-seropositive subjects do not develop higher vector-specific cellular immune responses as compared with Ad5-seronegative subjects after vaccination. These findings challenge the hypothesis that activated Ad5-specific T lymphocytes were the cause of the potential enhanced HIV-1 susceptibility in the STEP study. [ABSTRACT FROM AUTHOR]

The mechanisms underlying possible increased HIV-1 acquisition in adenovirus 5 (Ad5)-seropositive subjects vaccinated with Ad5–HIV-1 vectors in the Merck STEP trial remain unclear. We find that Ad5 serostatus does not predict Ad5-specific CD4+ T cell frequency, and we did not observe durable significant differences in Ad5-specific CD4+ T cells between Ad5-seropositive and Ad5-seronegative subjects after vaccination. These findings indicate no causative role for Ad5-specific CD4+ T cells in increasing HIV-1 susceptibility in the STEP trial. [ABSTRACT FROM AUTHOR]

• Antibody response correlating with vaccination was used to define seroresponse. • P-values from Fisher's exact test were used to compare definitions of seroresponse. • Two-fold rise and SSCO of 200 EU/mL best differentiated vaccine/placebo recipients. The recombinant vesicular stomatitis virus – Zaire Ebola virus envelope glycoprotein (rVSVΔG-ZEBOV-GP) vaccine is a live recombinant vesicular stomatitis virus (VSV) where the VSV G protein is replaced with ZEBOV-GP. To better understand the immune response after receiving the rVSVΔG-ZEBOV-GP vaccine, the current analyses evaluated different definitions of seroresponse that differentiate vaccine and placebo recipients enrolled in a placebo-controlled clinical trial (PREVAIL; NCT02344407) in which a subset of the study participants had elevated baseline titers. Alternative values for serostatus cutoff (SSCO; 200–500 EU/mL) and/or fold rise (two- to five-fold) were applied to compare their ability to distinguish between participants receiving rVSVΔG-ZEBOV-GP or placebo. The results indicate that an SSCO of 200 EU/mL can be used to define seropositivity at baseline (i.e. pre-vaccination). The use of dual criteria of the same SSCO (200 EU/mL) together with a two-fold rise in antibody level from baseline provided the definition of seroresponse that maximized the statistical significance between vaccine recipients and placebo recipients post-vaccination. Clinical trial registration: NCT02344407. [ABSTRACT FROM AUTHOR]

This review focuses on a dengue virus (DENV) vaccine candidate based on a recombinant subunit approach which targets the DENV envelope glycoprotein (E). Truncated versions of E consisting of the N-terminal portion of E (DEN-80E) have been expressed recombinantly in the Drosophila S2 expression system and shown to have native-like conformation. Preclinical studies demonstrate that formulations containing tetravalent DEN-80E adjuvanted with ISCOMATRIX™ adjuvant induce high titer virus neutralizing antibodies and IFN-γ producing T cells in flavivirus-naïve non-human primates. The preclinical data further suggest that administration of such formulations on a 0, 1, 6 month schedule may result in higher maximum virus neutralizing antibody titers and better durability of those titers compared to administration on a 0, 1, 2 month schedule. In addition, the virus neutralizing antibody titers induced by adjuvanted tetravalent DEN-80E compare favorably to the titers induced by a tetravalent live virus comparator. Furthermore, DEN-80E was demonstrated to be able to boost virus neutralizing antibody titers in macaques that have had a prior DENV exposure. A monovalent version of the vaccine candidate, DEN1-80E, was formulated with Alhydrogel™ and studied in a proof-of-principle Phase I clinical trial by Hawaii Biotech, Inc. ( NCT00936429 ). The clinical trial results demonstrate that both the 10 μg and 50 μg formulations of DEN1-80E with 1.25 mg of elemental aluminum were immunogenic when administered in a 3-injection series (0, 1, 2 months) to healthy, flavivirus-naïve adults. The vaccine formulations induced DENV-1 neutralizing antibodies in the majority of subjects, although the titers in most subjects were modest and waned over time. Both the 10 μg DEN1-80E and the 50 μg DEN1-80E formulations with Alhydrogel™ were generally well tolerated. [ABSTRACT FROM AUTHOR]