FLU-v, developed by PepTcell (SEEK), is a peptide vaccine aiming to provide a broadly protective cellular immune response against influenza A and B. A randomized, double-blind, placebo-controlled, single-center, phase IIb efficacy and safety trial was conducted. One hundred and fifty-three healthy individuals 18–55 years of age were randomized to receive one or two doses of adjuvanted FLU-v or adjuvanted placebo subcutaneously on days −43 and −22, prior to intranasal challenge on day 0 with the A/California/04/2009/H1N1 human influenza A challenge virus. The primary objective of the study was to identify a reduction in mild to moderate influenza disease (MMID) defined as the presence of viral shedding and clinical influenza symptoms. Single-dose adjuvanted FLU-v recipients (n = 40) were significantly less likely to develop MMID after challenge vs placebo (n = 42) (32.5% vs 54.8%p = 0.035). FLU-v should continue to be evaluated and cellular immunity explored further as a possible important correlate of protection against influenza.

Immunity to mosquito salivary proteins could provide protection against multiple mosquito-borne diseases and significantly impact public health. We evaluated the safety and immunogenicity of AGS-v PLUS, a mosquito salivary peptide vaccine, in healthy adults 18–50 years old. We conducted a randomized, double-blind, placebo-controlled Phase 1 study of AGS-v PLUS administered subcutaneously on Days 1 and 22 at the Center for Vaccine Development and Global Health, Baltimore, MD, USA. Participants were block randomized 1:1:1:1:1 to two doses saline placebo, two doses AGS-v PLUS, AGS-v PLUS/ISA-51 and saline placebo, two doses AGS-v PLUS/ISA-51, or two doses AGS-v PLUS/Alhydrogel. Primary endpoints were safety (all participants receiving ≥1 injection) and antibody and cytokine responses (all participants with day 43 samples), analysed by intention to treat. Between 26 August 2019 and 25 February 2020, 51 participants were enrolled and randomized, 11 into the single dose AGS-v PLUS/ISA-51 group and ten in other groups. Due to COVID-19, 15 participants did not return for day 43 samplings. Participants experienced no treatment-emergent or serious adverse events. All solicited symptoms in 2/10 placebo recipients and 22/41 AGS-v PLUS recipients after dose one and 1/10 placebo recipients and 22/41 AGS-v PLUS recipients after dose two were mild/moderate except for one severe fever the day after vaccination (placebo group). Only injection site pain was more common in vaccine groups (15/51 after dose 1 and 11/51 after dose 2) versus placebo. Compared to placebo, all vaccine groups had significantly greater fold change in anti-AGS-v PLUS IgG and IFN-ɣ from baseline. AGS-v PLUS had favourable safety profile and induced robust immune responses. Next steps will determine if findings translate into clinical efficacy against mosquito-borne diseases. 10.13039/501100000276 UK Department of Health and Social Care .

Previous reports demonstrated that FLU-v, a peptide-based broad-spectrum influenza vaccine candidate, induced antibody and cellular immune responses in humans. Here, we evaluate cellular effector functions and cross-reactivity. PBMC sampled pre- (day 0) and post-vaccination (days 42 and 180) from vaccine (n = 58) and placebo (n = 27) recipients were tested in vitro for responses to FLU-v and inactivated influenza strains (A/H3N2, A/H1N1, A/H5N1, A/H7N9, B/Yamagata) using IFN-γ and granzyme B ELISpot. FLU-v induced a significant increase in the number of IFN-γ- and granzyme-B-secreting cells responding to the vaccine antigens from pre-vaccination (medians: 5 SFU/10⁶ cells for both markers) to day 42 (125 and 40 SFU/10⁶ cells, p < 0.0001 for both) and day 180 (75 and 20 SFU/10⁶ cells, p < 0.0001 and p = 0.0047). The fold increase from pre-vaccination to day 42 for IFN-γ-, granzyme-B-, and double-positive-secreting cells responding to FLU-v was significantly elevated compared to placebo (medians: 16.3-fold vs. 1.0-fold, p < 0.0001; 3.5-fold vs. 1.0-fold, p < 0.0001; 3.0-fold vs. 1.0-fold, p = 0.0012, respectively). Stimulation of PBMC with inactivated influenza strains showed significantly higher fold increases from pre-vaccination to day 42 in the vaccine group compared to placebo for IFN-γ-secreting cells reacting to H1N1 (medians: 2.3-fold vs. 0.8-fold, p = 0.0083), H3N2 (1.7-fold vs. 0.8-fold, p = 0.0178), and H5N1 (1.7-fold vs. 1.0-fold, p = 0.0441); for granzyme B secreting cells reacting to H1N1 (3.5-fold vs. 1.0-fold, p = 0.0075); and for double positive cells reacting to H1N1 (2.9-fold vs. 1.0-fold, p = 0.0219), H3N2 (1.7-fold vs. 0.9-fold, p = 0.0136), and the B strain (2.0-fold vs. 0.8-fold, p = 0.0227). The correlation observed between number of cells secreting IFN-γ or granzyme B in response to FLU-v and to the influenza strains supported vaccine-induced cross-reactivity. In conclusion, adjuvanted FLU-v vaccination induced cross-reactive cellular responses with cytotoxic capacity, further supporting the development of FLU-v as a broad-spectrum influenza vaccine.

Background: The global health burden of mosquito-borne viruses, including dengue, yellow fever, Zika, and chikungunya, is rising due to climate change and globalisation, which favour mosquito habitat expansion. The genetic diversity of these viruses complicates the development of virus-specific vaccines or antivirals, highlighting the need for pan-viral strategies. As the common vector for these pathogens, mosquitoes and specifically their salivary proteins represent a promising target for such interventions. Mosquito saliva, secreted into the skin during biting, has immunomodulatory effects that can enhance host susceptibility to infection, but these mechanisms are not well defined in humans. Methods: The objective of this study was to determine whether AGS-v PLUS, a vaccine targeting mosquito salivary antigens, could modulate the human skin immune response to mosquito biting and potentially promote antiviral bystander immunity. In a Phase I trial, healthy volunteers were vaccinated with AGS-v PLUS (with or without adjuvant) or placebo, and three weeks later, they were exposed to bites from Aedes albopictus and Aedes aegypti mosquitoes. Skin biopsies from bitten and unbitten sites were analysed by transcriptomic profiling. Results: In placebo recipients, mosquito biting elicited a marked adaptive immune response at 48 h, characterised by CD4⁺ Th1 and CD8⁺ T cell signatures and leukocyte recruitment. While responses to Ae. aegypti and Ae. albopictus bites were broadly similar, those to Ae. albopictus were stronger. Vaccination with AGS-v PLUS, particularly with adjuvant, enhanced Th1 and CD8⁺ T cell-associated gene expression while suppressing pathways linked to neutrophilic inflammation and epithelial stress, which together may provide enhanced antiviral capacity. Conclusions: These findings demonstrate that targeting the host response to mosquito saliva via vaccination can reprogram the skin’s immune response to mosquito bites, supporting a novel and broadly applicable pan-viral strategy to mitigate the impact of arboviral diseases.

Background/Objectives: FLU-v is a peptide-based broad-spectrum influenza vaccine proven to induce humoral and cellular immune responses in humans. In this study, FLU-v-specific IgG1 and IgG3 subclass antibodies, induced by adjuvanted or non-adjuvanted FLU-v vaccination in healthy adults participating in a phase II clinical study, were quantitated. The ability of these antibodies to induce NK cell activation was investigated. Methods: An ELISA was developed to quantify FLU-v-specific IgG1 and IgG3 antibodies in serum. A flowcytometric assay based on an NK cell line was used to evaluate NK cell activation by expression of degranulation marker CD107a. Results: In the adjuvanted FLU-v group, IgG1 and IgG3 seroconversion on day 42 was 88.5% and 86.5% compared to 53.4% and 29.3% in the non-adjuvanted FLU-v group, which was significantly different from the respective placebo groups (0–6.3%). Adjuvanted FLU-v vaccination induced a raise in median IgG1 and IgG3 levels from 435 and 167 ng/mL pre vaccination to 4422 and 2020 ng/mL 42 days post vaccination, representing a fold increase of 16.3 for IgG1 and 11.6 for IgG3, which was sustained on day 180 post vaccination (10.4-fold and 5.0-fold, respectively). Non-adjuvanted vaccination induced a more modest increase in IgG1 and IgG3 from 655 and 206 ng/mL pre vaccination to 1808 and 264 ng/mL 42 days post vaccination. A correlation between levels of FLU-v-specific IgG, IgG1, or IgG3 and their ability to induce NK cell activation was demonstrated. Conclusions: A single dose of adjuvanted FLU-v induced high levels of long-lasting antigen-specific IgG1 and IgG3 antibodies with NK cell-mediated effector functions relevant to protection against influenza disease.

Background/Objectives: Coronaviruses are a family of positive-sense RNA viruses that cause respiratory and gastrointestinal disease in mammals and birds. Their zoonotic nature and high mutability make them a pandemic threat. UNICOR-v is a pre-pandemic, pan-coronavirus vaccine composed of an adjuvanted mix of twelve synthetic peptides originating from conserved regions within Nsp12 and M coronavirus proteins containing clusters of predicted T-cell epitopes. Here, we evaluate the immunogenicity of UNICOR-v and its efficacy against Middle East Respiratory Syndrome-related coronavirus (MERS). Methods: Animals were vaccinated with an adjuvanted equimolar mix of UNICOR-v. Humoral and cellular immunogenicity were assessed 28 days later through ELISA and FLUOROSpot. Vaccine efficacy was assessed in a DPP4 knock-in (HDPP4-KI) mouse model where mice were challenged post-vaccination with a lethal or non-lethal dose of MERS-CoV-MA. Results: Vaccination with UNICOR-v induced high IgG titers in both mice and rabbits and cellular secretion of pro-inflammatory cytokines. Vaccination with UNICOR-v, or passive serum transfer, significantly reduced viral lung titers 4 days post-infection compared to placebo. Vaccination induced lower immune cell infiltration in the alveolar space and increased repair of the cells lining the major airways in vaccinated mice, translating to increased survival rate compared to placebo. Conclusions: These data demonstrate the ability of conserved T-cell epitopes to protect against MERS-CoV infection, supporting further characterization of the breadth of protection of UNICOR-v against other coronaviruses that affect humans and livestock, following a One Health approach to control this highly zoonotic family of viruses.