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Zika virus (ZIKV), a mosquito-borne flavivirus, is a re-emerging virus that constitutes a public health threat due to its recent global spread, recurrent outbreaks, and infections that are associated with neurological abnormalities in developing fetuses and Guillain-Barré syndrome in adults. To date, there are no approved vaccines against ZIKV infection. Various preclinical and clinical development programs are currently ongoing in an effort to bring forward a vaccine for ZIKV. We have developed a ZIKV vaccine candidate based on Virus-Like-Particles (VLPs) produced in HEK293 mammalian cells using the prM (a precursor to M protein) and envelope (E) structural protein genes from ZIKV. Transient transfection of cells via plasmid and electroporation produced VLPs which were subsequently purified by column chromatography yielding approximately 2mg/L. Initially, immunogenicity and efficacy were evaluated in AG129 mice using a dose titration of VLP with and without Alhydrogel 2% (alum) adjuvant. We found that VLP with and without alum elicited ZIKV-specific serum neutralizing antibodies (nAbs) and that titers correlated with protection. A follow-up immunogenicity and efficacy study in rhesus macaques was performed using VLP formulated with alum. Multiple neutralization assay methods were performed on immune sera including a plaque reduction neutralization test, a microneutralization assay, and a Zika virus Renilla luciferase neutralization assay. All of these assays indicate that following immunization, VLP induces high titer nAbs which correlate with protection against ZIKV challenge. These studies confirm that ZIKV VLPs could be efficiently generated and purified. Upon VLP immunization, in both mice and NHPs, nAb was induced that correlate with protection against ZIKV challenge. These studies support translational efforts in developing a ZIKV VLP vaccine for evaluation in human clinical trials.

Zika virus (ZIKV) is a mosquito-borne flavivirus with maternal infection associated with preterm birth, congenital malformations, and fetal death, and adult infection associated with Guillain-Barré syndrome. Recent widespread endemic transmission of ZIKV and the potential for future outbreaks necessitate the development of an effective vaccine. We developed a ZIKV vaccine candidate based on virus-like-particles (VLPs) generated following transfection of mammalian HEK293T cells using a plasmid encoding the pre-membrane/membrane (prM/M) and envelope (E) structural protein genes. VLPs were collected from cell culture supernatant and purified by column chromatography with yields of approximately 1-2mg/L. To promote increased particle yields, a single amino acid change of phenylalanine to alanine was made in the E fusion loop at position 108 (F108A) of the lead VLP vaccine candidate. This mutation resulted in a modest 2-fold increase in F108A VLP production with no detectable prM processing by furin to a mature particle, in contrast to the lead candidate (parent). To evaluate immunogenicity and efficacy, AG129 mice were immunized with a dose titration of either the immature F108A or lead VLP (each alum adjuvanted). The resulting VLP-specific binding antibody (Ab) levels were comparable. However, geometric mean neutralizing Ab (nAb) titers using a recombinant ZIKV reporter were significantly lower with F108A immunization compared to lead. After virus challenge, all lead VLP-immunized groups showed a significant 3- to 4-Log 10 reduction in mean ZIKV RNAemia levels compared with control mice immunized only with alum, but the RNAemia reduction of 0.5 Log 10 for F108A groups was statistically similar to the control. Successful viral control by the lead VLP candidate following challenge supports further vaccine development for this candidate. Notably, nAb titer levels in the lead, but not F108A, VLP-immunized mice inversely correlated with RNAemia. Further evaluation of sera by an in vitro Ab-dependent enhancement assay demonstrated that the F108A VLP-induced immune sera had a significantly higher capacity to promote ZIKV infection in FcγR-expressing cells. These data indicate that a single amino acid change in the fusion loop resulted in increased VLP yields but that the immature F108A particles were significantly diminished in their capacity to induce nAbs and provide protection against ZIKV challenge.

Influenza virus remains a significant health and social concern in part because of newly emerging strains, such as avian H5N1 virus. We have developed a prototype H5N1 vaccine using a recombinant, replication-competent Adenovirus serotype 4 (Ad4) vector, derived from the U.S. military Ad4 vaccine strain, to express the hemagglutinin (HA) gene from A/Vietnam/1194/2004 influenza virus (Ad4-H5-Vtn). Our hypothesis is that a mucosally-delivered replicating Ad4-H5-Vtn recombinant vector will be safe and induce protective immunity against H5N1 influenza virus infection and disease pathogenesis. The Ad4-H5-Vtn vaccine was designed with a partial deletion of the E3 region of Ad4 to accommodate the influenza HA gene. Replication and growth kinetics of the vaccine virus in multiple human cell lines indicated that the vaccine virus is attenuated relative to the wild type virus. Expression of the HA transgene in infected cells was documented by flow cytometry, western blot analysis and induction of HA-specific antibody and cellular immune responses in mice. Of particular note, mice immunized intranasally with the Ad4-H5-Vtn vaccine were protected against lethal H5N1 reassortant viral challenge even in the presence of pre-existing immunity to the Ad4 wild type virus. Several non-clinical attributes of this vaccine including safety, induction of HA-specific humoral and cellular immunity, and efficacy were demonstrated using an animal model to support Phase 1 clinical trial evaluation of this new vaccine.

Designing immunogens and improving delivery methods eliciting protective immunity is a paramount goal of HIV vaccine development. A comparative vaccine challenge study was performed in rhesus macaques using clade C HIV Envelope (Env) and SIV Gag antigens. One group was vaccinated using co-immunization with DNA Gag and Env expression plasmids cloned from a single timepoint and trimeric Env gp140 glycoprotein from one of these clones (DNA+Protein). The other group was a prime-boost regimen composed of two replicating simian (SAd7) adenovirus-vectored vaccines expressing Gag and one Env clone from the same timepoint as the DNA+Protein group paired with the same Env gp140 trimer (SAd7+Protein). The env genes were isolated from a single pre-peak neutralization timepoint approximately 1 year post infection in CAP257, an individual with a high degree of neutralization breadth. Both DNA+Protein and SAd7+Protein vaccine strategies elicited significant Env-specific T cell responses, lesser Gag-specific responses, and moderate frequencies of Env-specific T FH cells. Both vaccine modalities readily elicited systemic and mucosal Env-specific IgG but not IgA. There was a higher frequency and magnitude of ADCC activity in the SAd7+Protein than the DNA+Protein arm. All macaques developed moderate Tier 1 heterologous neutralizing antibodies, while neutralization of Tier 1B or Tier 2 viruses was sporadic and found primarily in macaques in the SAd7+Protein group. Neither vaccine approach provided significant protection from viral acquisition against repeated titered mucosal challenges with a heterologous Tier 2 clade C SHIV. However, lymphoid and gut tissues collected at necropsy showed that animals in both vaccine groups each had significantly lower copies of viral DNA in individual tissues compared to levels in controls. In the SAd7+Protein-vaccinated macaques, total and peak PBMC viral DNA were significantly lower compared with controls. Taken together, this heterologous Tier 2 SHIV challenge study shows that combination vaccination with SAd7+Protein was superior to combination DNA+Protein in reducing viral seeding in tissues in the absence of protection from infection, thus emphasizing the priming role of replication-competent SAd7 vector. Despite the absence of correlates of protection, because antibody responses were significantly higher in this vaccine group, we hypothesize that vaccine-elicited antibodies contribute to limiting tissue viral seeding.

PXVX0047 is an investigational vaccine developed for active immunization to prevent febrile acute respiratory disease (ARD) caused by adenovirus serotypes 4 (Ad4) and 7 (Ad7). PXVX0047 consists of a modernized, plasmid-derived vaccine that was generated using a virus isolated from Wyeth Ad4 and Ad7 vaccine tablets. A phase 1 two-arm, randomized, double-blind, active-controlled study was conducted to evaluate the safety profile and immunogenicity of the investigational adenovirus vaccines. The two components of PXVX0047 were administered orally together in a single dose to 11 subjects. For comparison, three additional subjects received the Ad4/Ad7 vaccine that is currently in use by the US military. The results of this study show that the tolerability and immunogenicity of the PXVX0047 Ad7 component are comparable with that of the control Ad4/Ad7 vaccine; however, the immunogenicity of the PXVX0047 Ad4 component was lower than expected. Clinical trial number NCT03160339.

There is a well-acknowledged need for an effective AIDS vaccine that protects against HIV-1 infection or limits in vivo viral replication. The objective of these studies is to develop a replication-competent, vaccine vector based on the adenovirus serotype 4 (Ad4) virus expressing HIV-1 envelope (Env) 1086 clade C glycoprotein. Ad4 recombinant vectors expressing Env gp160 (Ad4Env160), Env gp140 (Ad4Env140), and Env gp120 (Ad4Env120) were evaluated. The recombinant Ad4 vectors were generated with a full deletion of the E3 region of Ad4 to accommodate the env gene sequences. The vaccine candidates were assessed in vitro following infection of A549 cells for Env-specific protein expression and for posttranslational transport to the cell surface as monitored by the binding of broadly neutralizing antibodies (bNAbs). The capacity of the Ad4Env vaccines to induce humoral immunity was evaluated in rabbits for Env gp140 and V1V2-specific binding antibodies, and HIV-1 pseudovirus neutralization. Mice immunized with the Ad4Env160 vaccine were assessed for IFNγ T cell responses specific for overlapping Env peptide sets. Robust Env protein expression was confirmed by western blot analysis and recognition of cell surface Env gp160 by multiple bNAbs. Ad4Env vaccines induced humoral immune responses in rabbits that recognized Env 1086 gp140 and V1V2 polypeptide sequences derived from 1086 clade C, A244 clade AE, and gp70 V1V2 CASE A2 clade B fusion protein. The immune sera efficiently neutralized tier 1 clade C pseudovirus MW965.26 and neutralized the homologous and heterologous tier 2 pseudoviruses to a lesser extent. Env-specific T cell responses were also induced in mice following Ad4Env160 vector immunization. The Ad4Env vaccine vectors express high levels of Env glycoprotein and induce both Env-specific humoral and cellular immunity thus supporting further development of this new Ad4 HIV-1 Env vaccine platform in Phase 1 clinical trials.

Chikungunya virus (CHIKV) disease is an ongoing public health threat. We aimed to evaluate the safety and immunogenicity of PXVX0317, an aluminium hydroxide-adjuvanted formulation of a CHIKV virus-like particle (VLP) vaccine. This randomised, double-blind, parallel-group, phase 2 trial was conducted at three clinical trial centres in the USA. Eligible participants were healthy CHIKV-naïve adults aged 18–45 years. Participants were stratified by site and randomly assigned (1:1:1:1:1:1:1:1) to one of the eight vaccination groups using a block size of 16. Group 1 received two doses of unadjuvanted PXVX0317 28 days apart (2 × 20 μg; standard); all other groups received adjuvanted PXVX0317: groups 2–4 received two doses 28 days apart (2 × 6 μg [group 2], 2 × 10 μg [group 3], or 2 × 20 μg [group 4]; standard); group 4 also received a booster dose 18 months after the first active injection (40 μg; standard plus booster); groups 5–7 received two doses 14 days apart (2 × 6 μg [group 5], 2 × 10 μg [group 6], or 2 × 20 μg [group 7]; accelerated); and group 8 received one dose (1 × 40 μg; single). The primary endpoint was the geometric mean titre of anti-CHIKV neutralising antibody on day 57 (28 days after the last vaccination), assessed in the immunogenicity-evaluable population. Additionally, we assessed safety. This trial is registered at ClinicalTrials.gov, NCT03483961. This trial was conducted from April 18, 2018, to Sept 21, 2020; 468 participants were assessed for eligibility. Of these, 415 participants were randomly assigned to eight groups (n=53 in groups 1, 5, and 6; n=52 in groups 2 and 8; n=51 in groups 3 and 7; and n=50 in group 4) and 373 were evaluable for immunogenicity. On day 57, serum neutralising antibody geometric mean titres were 2057·0 (95% CI 1584·8–2670·0) in group 1, 1116·2 (852·5–1461·4; p=0·0015 vs group 1 used as a reference) in group 2, 1465·3 (1119·1–1918·4; p=0·076) in group 3, 2023·8 (1550·5–2641·7; p=0·93) in group 4, 920·1 (710·9–1190·9; p<0·0001) in group 5, 1206·9 (932·4–1562·2; p=0·0045) in group 6, 1562·8 (1204·1–2028·3; p=0·14) in group 7, and 1712·5 (1330·0–2205·0; p=0·32) in group 8. In group 4, a booster dose increased serum neutralising antibody geometric mean titres from 215·7 (95% CI 160·9–289·1) on day 547 to 10 941·1 (7378·0–16 225·1) on day 575. Durability of the immune response (evaluated in groups 1, 4, and 8) was shown up to 2 years. The most common solicited adverse event was pain at the injection site, reported in 12 (23%) of 53 participants who received the unadjuvanted vaccine (group 1) and 111 (31%) of 356 who received the adjuvanted vaccine. No vaccine-related serious adverse events were reported. PXVX0317 was well tolerated and induced a robust and durable serum neutralising antibody immune response against CHIKV up to 2 years. A single 40 μg injection of adjuvanted PXVX0317 is being further investigated in phase 3 clinical trials (NCT05072080 and NCT05349617). Emergent BioSolutions.

Chikungunya disease is a growing global public health concern. Vimkunya (previously chikungunya virus virus-like particle vaccine, previously PXVX0317) is a single-dose, pre-filled syringe for intramuscular injection. Here, we report safety, tolerability, and immunogenicity data for Vimkunya versus placebo in healthy adolescents and adults aged 12–64 years, and evaluate lot-to-lot consistency. This pivotal phase 3, randomised, double-blind, placebo-controlled, parallel-group trial was done at 47 clinical trial sites in the USA. Eligible participants were healthy adolescents and adults aged 12–64 years. Participants were divided into three age strata (12–17 years, 18–45 years, and 46–64 years) within each site and randomly assigned (2:2:2:1) to receive one of three consecutively manufactured lots of Vimkunya or placebo (same excipient composition without chikungunya virus virus-like particle or aluminium hydroxide components) on study day 1. Neither participants, nor clinical site personnel, nor the funder knew participants' individual treatment assignments until all participants completed their involvement in the trial and the database was cleaned and locked. Participants attended a screening visit, followed by a day 1 visit that included random assignment, blood sample collection, and administration of a single dose of Vimkunya or placebo by intramuscular injection in the deltoid muscle. The coprimary endpoints were: the difference in chikungunya virus serum neutralising antibody seroreponse rate (vaccine minus placebo) at day 22; chikungunya virus serum neutralising antibody geometric mean titre (GMT) at day 22 for vaccine and placebo; and chikungunya virus serum neutralising GMT ratio at day 22 between all three pairs of vaccine lots (A:B, B:C, and A:C) in adults aged 18–45 years. The trial is registered with ClinicalTrials.gov, NCT05072080 and EudraCT, 2023-001124-42. Between Sept 29, 2021, and Sept 23, 2022, 4215 participants were screened, of whom 3258 were eligible and enrolled (1667 [51·2%] female and 1591 [48·8%] male), and 3254 (99·9%) received either Vimkunya (n=2790) or placebo (n=464). The immunogenicity evaluable population included 2983 participants, of whom 2559 received Vimkunya and 424 received placebo. At day 22, 2503 (97·8%) of 2559 participants in the Vimkunya group had a seroresponse, compared with five (1·2%) of 424 participants in the placebo group for the immunogenicity evaluable population. The seroreponse rate difference was 96·6% (95% CI 95·0–97·5; p<0·0001). In the immunogenicity evaluable population, chikungunya virus serum neutralising antibody GMT at day 22 for the vaccine group was 1618 and for the placebo group was 7·9 (p<0·0001). At day 22, the serum neutralising GMT ratios for the pairs of lots (A:B, B:C, and A:C) were 0·98 (95% CI 0·85–1·14), 0·97 (0·84–1·12), and 0·95 (0·82–1·10), respectively. Vimkunya had a favourable safety profile; most adverse events were self-limiting and grade 1 or 2 in severity. The most common adverse events were injection site pain (656 [23·7%] of 2764 participants in the vaccine group), fatigue (551 [19·9%] of 2764), headache (498 [18·0%] of 2765), and myalgia (486 [17·6%] of 2764). Vimkunya induces a rapid and robust immune response. These findings support the potential for this vaccine to protect individuals aged 12–64 years from disease caused by chikungunya virus. Emergent BioSolutions and Bavarian Nordic.

Adults older than 65 years are at increased risk for atypical presentations of chikungunya disease, as well as for severe outcomes including death. In this phase 3, randomised, double-blind, placebo-controlled, parallel-group trial, adults aged 65 years and older received a single intramuscular dose of Vimkunya (previously chikungunya virus virus-like particle vaccine) or placebo at ten sites in the USA. Participants, clinical site personnel, and the sponsor were masked to individual treatment assignments until all participants had completed their involvement in the trial and the database was cleaned and locked. Baseline and postvaccination chikungunya virus serum neutralising antibody (SNA) titres (NT80) were assessed at selected timepoints. Safety was assessed up to 183 days after dose administration in all participants from the exposed population who provided safety assessment data. This trial is registered with ClinicalTrials.gov, NCT05349617, and is completed. Between May 12 and Dec 2, 2022, 413 participants were recruited and randomly assigned (1:1) to receive the Vimkunya vaccine (n=206) or placebo (n=207). The coprimary endpoints of immunologic superiority of chikungunya virus SNA titres compared with placebo and geometric mean titre at day 22 were met. Vimkunya induced a protective seroresponse (SNA NT80≥100, considered the presumptive seroprotective antibody response) in 149 (82%) of 181 participants (95% CI 76·1–87·2) at day 15, in 165 (87%) of 189 participants (81·8–91·3) at day 22, and in 139 (76%) of 184 participants (68·9–81·2) at day 183. Although there was a slightly higher early immune response in the 65–74 years age group at day 15 compared with the 75 years and older age group, the seroresponse rates at day 22 and day 183 were similar. There were no notable differences in adverse event rates between groups, and most adverse events were grade 1 or 2 in severity and of short duration. No vaccine-related serious adverse events or deaths occurred. We provide robust data from adults aged 65 years and older showing that Vimkunya is well tolerated and can provide a high rate of protection within 2 weeks postvaccination and during 6 months of follow-up. Emergent BioSolutions and Bavarian Nordic.

In a phase 2 safety and immunogenicity study of a chikungunya virus virus-like particle (CHIKV VLP) vaccine in an endemic region, of 400 total participants, 78 were found to be focus reduction neutralizing antibody seropositive at vaccination despite being ELISA seronegative at screening, of which 39 received vaccine. This post hoc analysis compared safety and immunogenicity of CHIKV VLP vaccine in seropositive (n = 39) versus seronegative (n = 155) vaccine recipients for 72 weeks post-vaccination. There were no differences in solicited adverse events, except injection site swelling in 10.3% of seropositive versus 0.6% of seronegative recipients (p = 0.006). Baseline seropositive vaccine recipients had stronger post-vaccination luciferase neutralizing antibody responses versus seronegative recipients (peak geometric mean titer of 3594 and 1728, respectively) persisting for 72 weeks, with geometric mean fold increases of 3.1 and 13.2, respectively. In this small study, CHIKV VLP vaccine was well-tolerated and immunogenic in individuals with pre-existing immunity. ClinicalTrials.gov Identifier: NCT02562482.