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Abstract Background Over the past 20 years, over 5 million cases of chikungunya, a mosquito-transmitted viral disease, have been reported in over 110 countries. Until recently, preventative strategies for chikungunya were largely ineffective, relying on vector control and individual avoidance of mosquito bites. Methods This review outlines the preclinical and clinical efficacy and safety data that led to the approval of VLA1553 (IXCHIQ®), a live-attenuated vaccine against chikungunya disease. It also describes the innovative development pathway of VLA1553, based on an immunological surrogate of protection, and discusses ongoing and future post-licensure studies. Results In mice and non-human primate models, VLA1553 elicited high titres of neutralizing antibodies, conferred protection against wild-type chikungunya virus challenge and raised no safety concerns. A Phase 1 clinical trial of VLA1553 demonstrated 100% seroconversion among 120 healthy participants, with sustained neutralizing antibody titres after 12 months. These results and determination of a surrogate marker of protection led to advancement of VLA1553 directly into Phase 3 clinical development, as agreed with the US Food and Drug Administration (FDA) and the European Medicines Agency. The pivotal Phase 3 trial met its primary immunogenicity endpoint, achieving seroprotective levels based on immuno-bridging in baseline seronegative participants 28 days post-vaccination. These findings enabled submission of a Biologics Licence Application to the FDA for accelerated approval of VLA1553 in the US for adults aged ≥18 years. Ongoing and planned studies will confirm the clinical efficacy/effectiveness and safety of VLA1553 in adults and younger individuals, and will generate data in chikungunya endemic countries that have the highest unmet need. Conclusion VLA1553 is the first vaccine approved for the prevention of chikungunya disease in adults, following accelerated development based on a serological surrogate marker of protection. VLA1553 adds to strategies to reduce the spread and burden of chikungunya in endemic populations and travellers.

Background Chikungunya virus (CHIKV) is a mosquito-transmitted, arthritogenic alphavirus that causes sporadic outbreaks of often debilitating rheumatic disease. The recently approved CHIKV vaccine, IXCHIQ, is based on a live-attenuated CHIKV strain (VLA1553), with viraemic vaccine recipients theoretically able to transmit VLA1553 to mosquitoes with ensuing onward transmission. We thus evaluated VLA1553 transmission from artificial blood meals to Aedes albopictus mosquitoes, and onward transmission to mice. Methods Female A. albopictus mosquitoes were fed on defibrinated sheep blood containing wild-type CHIKV (viral titre: 7.50 log 10 CCID 50 /mL) or VLA1553 (viral titres: 7.85, 5.72, 4.58, and 3.79 log 10 CCID 50 /mL). Viral titres in mosquito bodies and saliva were determined using CCID 50 assays 7–8 days after the blood meal. After providing CHIKV or VLA1553 (viral titres ~ 7–8 log 10 CCID 50 /mL) in blood meals to mosquitoes, infected mosquitoes were fed on highly susceptible Irf3/7 −/− mice ( n  = 3 per group). Data were re-analysed using the same reverse transcription quantitative polymerase chain reaction (RT-qPCR) as for an earlier VLA1553 phase 1 clinical trial, to allow correlations between blood meal titres and viraemia in vaccine recipients. Results Mosquito body viral titres were significantly higher ( P  < 0.0001) for CHIKV versus VLA1553-fed mosquitoes at blood meal viral titres of ~ 7–8 log 10 CCID 50 /mL. Mosquito body VLA1553 titres decreased with reducing blood meal titres, but there was no dose-dependent effect on saliva viral titres. No dissemination to salivary glands was seen at blood meal titres ≤ 3.875 log 10 CCID 50 /mL. CHIKV-fed mosquitoes were able to transmit virus, and induce viraemia in, 3/3 Irf3/7 −/− mice via mosquito bites. In contrast, 0/3 Irf3/7 −/− mice became infected after bites from VLA1553-fed mosquitoes. RT-qPCR comparisons with phase 1 clinical data for VLA1553-vaccinated individuals indicated that VLA1553 viraemia was at or below the aforementioned threshold for transmission. Conclusions The evidence presented herein argue that the low viraemia in VLA1553-vaccinated individuals would mitigate against transmission. In addition, replication of VLA1553 in mosquito bodies was also significantly attenuated. Overall, mosquito-borne transmission of VLA1553 from vaccinated individuals to others appears improbable. Graphical Abstract

Chikungunya virus (CHIKV) is a reemerging mosquito-borne alphavirus responsible for numerous outbreaks. Chikungunya can cause debilitating acute and chronic disease. Thus, the development of a safe and effective CHIKV vaccine is an urgent global health priority. This study evaluated the effectiveness of the live-attenuated CHIKV vaccine VLA1553 against WT CHIKV infection by using passive transfer of sera from vaccinated volunteers to nonhuman primates (NHP) subsequently exposed to WT CHIKV and established a serological surrogate of protection. We demonstrated that human VLA1553 sera transferred to NHPs conferred complete protection from CHIKV viremia and fever after challenge with homologous WT CHIKV. In addition, serum transfer protected animals from other CHIKV-associated clinical symptoms and from CHIKV persistence in tissue. Based on this passive transfer study, a 50% micro–plaque reduction neutralization test titer of ≥ 150 was determined as a surrogate of protection, which was supported by analysis of samples from a seroepidemiological study. In conclusion, considering the unfeasibility of an efficacy trial due to the unpredictability and explosive, rapidly moving nature of chikungunya outbreaks, the definition of a surrogate of protection for VLA1553 is an important step toward vaccine licensure to reduce the medical burden caused by chikungunya.

Chikungunya disease, which results in incapacitating arthralgia, has been reported worldwide. We developed a live-attenuated chikungunya virus (CHIKV) vaccine candidate designed for active immunisation of the general population living in endemic regions, as well as serving as a prophylactic measure for travellers to endemic areas. This single-blind, randomised, dose-escalation, phase 1 study investigated as primary outcome safety of a live-attenuated CHIKV vaccine candidate. At two professional clinical trial centres in Illinois and Alabama, USA, healthy volunteers aged 18–45 years were randomly assigned (1:1:2) to one of three escalating dose groups (low dose 3·2 × 103 per 0·1 mL; medium dose 3·2 × 104 per 1 mL; or high dose 3·2 × 105 50% tissue culture infection dose per 1 mL) and received a single-shot immunisation on day 0. Individuals in all groups were revaccinated with the highest dose on either month 6 or 12, and followed up for 28 days after revaccination. The safety analysis included all individuals who received the single vaccination; the immunogenicity analysis, which was a secondary outcome, included all individuals who completed the study without major protocol deviations (per-protocol population). The study is registered with ClinicalTrials.gov, NCT03382964, and is complete. The study was done between March 5, 2018, and Jul 23, 2019, with 120 adults recruited and enrolled between March 5 and June 21, 2018, and assigned to receive a low (n=31), medium (n=30), or high (n=59) dose of the vaccine. The vaccine was safe in the high-dose group and well tolerated in the low-dose and medium-dose groups. Four (7%) of 59 vaccinees in the high-dose group reported any local reaction, and 11 (36%), 12 (40%), and 40 (68%) volunteers in the low-dose, medium-dose, and high-dose groups, respectively, reported any solicited systemic reaction. No vaccine-related serious adverse events were reported. Data up to month 12 after a single immunisation of the 120 healthy volunteers showed a good immunogenicity profile with 100% seroconversion rates achieved at day 14 (103 [100%] of 103) and sustained for 1 year across all dose groups. Mean peak antibody titres at day 28 ranged from 592·6 to 686·9 geometric mean titres from the low-dose to high-dose groups, respectively. A single vaccination was sufficient to induce sustaining high-titre neutralising antibodies, as shown by the absence of an anamnestic response after any revaccination ranging from 94% to 100% of participants. Following revaccination, vaccinees were protected from vaccine-induced viraemia. A novel live-attenuated CHIKV vaccine was well tolerated and highly immunogenic in an adult population and could be an effective intervention for prophylaxis of chikungunya disease worldwide. Valneva, Vienna, Austria; Coalition for Epidemic Preparedness Innovation and EU Horizon 2020.

Lyme disease is a growing public health concern that is geographically focused in regions where ticks that carry the causative bacteria, Borrelia burgdorferi sensu lato (s.l.), are endemic. Outer surface protein A (OspA) is expressed by B. burgdorferi s.l. spirochetes during the tick phase and OspA antibodies introduced during tick feeding can block transmission and prevent B. burgdorferi infection. Candidate Lyme disease vaccine VLA15 is comprised of the C-terminal domains of the six B. burgdorferi s.l. OspA serotypes (ST) prevalent in North America and Europe. We report herein that non-human primates immunized with VLA15 were protected against challenge with Ixodes scapularis ticks bearing B. burgdorferi sensu stricto (s.s.) (OspA ST1). Levels of residual B. burgdorferi s.s. tick colonization were reduced in ticks that fed on VLA15-immunized primates compared to those immunized with full length-OspA ST1 (FL-OspA) at a point when OspA-binding IgG levels were similar. Furthermore, monoclonal antibodies targeting the C-terminal half of OspA, elicited by FL-OspA immunization in primates, were more effective at complement-mediated bactericidal killing in vitro and clearance of spirochetes in ticks versus those directed against other parts of the protein. •VLA15 immunization protected NHPs against challenge with Ixodes ticks bearing B. burgdorferi ss (OspA ST1).•Post-challenge tick colonization levels were reduced in VLA15-immunized NHPs compared to levels in FL-OspA-immunized NHPs, despite similar anti-OspA IgG levels between the two vaccine groups.•Monoclonal antibodies targeting the C-terminal and central domains of OspA ST1 bound cell-associated OspA and manifested greater functional activity in vitro, and in vivo in mice challenged with Ixodes ticks bearing B. burgdorferi ss.

High-grade serous ovarian cancer (HGSOC) is currently treated with cytoreductive surgery and platinum-based chemotherapy. The majority of patients show a primary response; however, many rapidly develop drug resistance. Antiestrogens have been studied as low toxic treatment options for HGSOC, with higher response rates in platinum-sensitive cases. Mechanisms for this difference in response remain unknown. Therefore, the present study investigated the impact of platinum resistance on steroid metabolism in six established HGSOC cell lines sensitive and resistant against carboplatin using a high-resolution mass spectrometry assay to simultaneously quantify the ten main steroids of the estrogenic metabolic pathway. An up to 60-fold higher formation of steroid hormones and their sulfated or glucuronidated metabolites was observed in carboplatin-sensitive cells, which was reversible by treatment with interleukin-6 (IL-6). Conversely, treatment of carboplatin-resistant cells expressing high levels of endogenous IL-6 with the monoclonal anti-IL-6R antibody tocilizumab changed their status to “platinum-sensitive”, exhibiting a decreased IC50 value for carboplatin, decreased growth, and significantly higher estrogen metabolism. Analysis of these metabolic differences could help to detect platinum resistance in HGSOC patients earlier, thereby allowing more efficient interventions.