Recently, a phase 3 clinical trial published at The Lancet showed high immunogenicity and good safety profile of a one shot of a live attenuated Chikungunya (CHIK) vaccine (1), leading to further look for further approval of a CHIK vaccine first time in history.
CHIK is s a mosquito-borne viral disease caused by the Chikungunya virus (CHIKV), an RNA virus in the alphavirus genus of the family Togaviridae. The name Chikungunya derives from a word in the Kimakonde language, meaning “to become contorted”. It is transmitted by mosquitoes, most commonly Aedes aegypti and Aedes albopictus, which can also transmit Dengue and Zika viruses. These mosquitoes bite primarily during daylight hours. They lay eggs in containers with standing water. Both species feed outdoors, and Ae. aegypti also feeds indoors (2,3).
When an uninfected mosquito feeds on a person who has CHIKV circulating in their blood, the mosquito can ingest the virus. The virus then replicates in the mosquito over several days, gets to its salivary glands, and can be transmitted into a new human host when the mosquito bites them. The virus again begins to replicate in this newly infected person and reaches high concentrations in their blood, at which point they can further infect other mosquitoes and perpetuate the transmission cycle (3).
In symptomatic patients, the incubation period of CHIKV is 4–8 days after the bite of an infected mosquito. It is characterized by an abrupt onset of fever, frequently accompanied by severe joint pain. The joint pain is often debilitating and usually lasts for a few days but may be prolonged, lasting for weeks, months or even years. Other common signs and symptoms include joint swelling, muscle pain, headache, nausea, fatigue, and rash. Since these symptoms overlap with other infections, including those with Dengue and Zika viruses, cases can be misdiagnosed. In the absence of significant joint pain, symptoms in infected individuals are usually mild and the infection may go unrecognized (3).
Most patients recover fully from the infection; however, occasional cases of eye, heart, and neurological complications have been reported with CHIKV infections. Patients at extremes of the age spectrum are at higher risk for severe disease. Newborns infected during delivery and older people with underlying medical conditions may become severely ill and CHIKV infection can increase the risk of death. Once an individual is recovered, available evidence suggests they are likely to be immune from future infections (3).
The diagnosis of CHIK is usually by RT-PCR, though serologic tests can also be performed (2,3).
From the epidemiologic perspective, CHIKV leads to over 2 million cases reported since 2005 and has particularly been identified in over 110 countries in Asia, Africa, Europe, and the Americas (2,3). Historically, CHIKV has been endemic in tropical and subtropical regions of sub-Saharan Africa and Southeast Asia, where two distinct CHIKV transmission cycles exist. CHIKV is maintained in a rural enzootic transmission cycle, which occurs between various forest or savannah Aedes mosquitoes and animal reservoirs, with nonhuman primates being the presumed major reservoir host (3). Occasional introduction of the virus into urban areas is thought to cause periodic outbreaks of CHIKV disease (3). Urban transmission is mediated primarily by Aedes aegypti or Aedes albopictus mosquitoes and occurs in a human-mosquito-human transmission cycle (3). Although is not a common lethal disease (~0.1% mortality), these outbreaks can lead to a high socioeconomic burden since, but manifestations of CHIKV infection that lead to acute and chronic disability have considerable implications, including a substantial impact on quality of life for infected patients as well as considerable economic and community consequences (3).
As with Dengue and Zika, treatment of CHIK is symptomatic, with no current available antivirals. The only preventive methods are mosquito-control activities, and no current vaccine was available, until now (2,3).
Recent CHIK outbreak in Paraguay, and the emergence of new concepts of CHIK disease:
During October 1, 2022–March 11, 2023, a total of 81,037 suspected, probable, or confirmed CHIK cases was recorded by the Paraguayan Ministry of Health; among these, 75,911 (94%) occurred during 2023. Most cases occurred in the Central Department (49,070; 61%) and Asuncion (16,094; 20%). Cumulative national incidence was 1,073 cases per 100,000 population (3,088 per 100,000 population in Asuncion). Weekly case counts in Asuncion and Central Department declined slightly after epidemiologic week 6, but an increasing number and proportion of cases were subsequently reported from outlying regions, including along borders with Brazil and Argentina (4).
Among 47,116 probable or confirmed cases, 27,147 (58%) were in females, and the median age was 36 years (range = 0 days–103 years); 4,604 (10%) hospitalizations and 52 (<1%) deaths attributable to CHIKV infection were reported. Among 208 (0.4%) cases in infants aged ≤29 days (newborns), 140 hospitalizations and eight deaths were reported, accounting for the highest case fatality rate (3.8%) among all age groups. Among fatal neonatal cases, the timing of symptom onset suggested intrapartum transmission in 75%, and mosquito borne transmission in 25%, indeed a concerning concept in CHIK transmission. Among adults aged ≥60 years, 10,617 cases and 1,878 hospitalizations (41% of all hospitalizations) were reported. Within this group, 32 deaths occurred; 23 (72%) and 13 (41%) deceases had documented cardiovascular disease and diabetes, respectively, and 20 (63%) had two or more comorbidities. The highest case fatality rate among adults aged ≥60 years occurred among those aged ≥80 years (0.6%; 11 of 1,719 cases) (4).
Research and Development (R&D) for a CHIK vaccine has several difficulties, leading to new solutions:
- Though endemic in many countries, the highest relevant impact of the disease is during outbreaks. The continuous threat of CHIK (re-)emergence and the huge public health and economic impact of the epidemics and outbreaks, makes the development of a safe and effective vaccine a priority.
- In general, vaccine efficacy can be measured using three different parameters: (a) protection against local and/or systemic virus replication, (b) protection from development of clinical disease, and (c) development of an anamnestic response following challenge. For CHIK, some experts said that the lethal-arthritis (mouse) model is the most appropriate for prediction of vaccine efficacy in humans because it utilizes the extreme susceptibility of the immunodeficient mouse while allowing the simultaneous testing of the largest number of efficacy parameters, namely mortality, foot swelling, viremia, viral persistence in target organs, levels of IL-6 (and other cytokines) and ferritin. However, none of the above can contemplate feasibility, precision, and cost-effectiveness, altogether (5).
- Hence, developing a phase 3 Clinical Trial looking for efficacy it is evidently unfeasible, since also outbreaks are unpredictable, however, in countries where Aedes is present, a persistent and latent risk, the recent experience in Paraguay evidently leads us that early intervention could it lead to a lesser extent of cases, mortality, and sequelae.
- A “phase 3” Clinical Trial searching for a surrogate of protection is indeed the best option. Accordingly, a longitudinal cohort study performed in Cebu City, Philippines (6) found that the presence of pre-existing chikungunya virus (CHIKV) neutralizing antibodies (NAb) was associated with a decreased risk of symptomatic CHIKV infection. Among 854 participants who completed the 12-month visit (year 1) and 765 who completed the 24-month visit (year 2), 25 symptomatic CHIKV infections and 104 subclinical seroconversions occurred among 615 individuals with no detectable pre-year NAb in year 1 and 444 in year 2, while no symptomatic infections and one subclinical seroconversion occurred in those with a pre-year PRNT80 (plaque reduction neutralization test) titer ≥1:10. Pre-year PRNT80 titer ≥1:10 was associated with zero relative risk of symptomatic CHIKV infection and 0.018 risk of subclinical seroconversion in real life (6).
On June 24th, 2023, VLA1553, a live-attenuated vaccine candidate for active immunization and prevention of disease caused by CHIKV was tested in a phase 3 Clinical Trial searching for safety and immunogenicity, funded by Valneva, Coalition for Epidemic Preparedness Innovation (CEPI), and EU Horizon 2020 (1). Accordingly, 4128 participants were enrolled and randomized (3093 to VLA1553 and 1035 to placebo). 358 participants in the VLA1553 group and 133 participants in the placebo group discontinued before trial end. The per-protocol population for immunogenicity analysis comprised 362 participants (266 in the VLA1553 group and 96 in the placebo group). After a single vaccination, VLA1553 induced seroprotective CHIKV NAb levels (PRNT80 titer ≥1:10) in 263 (98·9%) of 266 participants in the VLA1553 group (95% CI 96·7–99·8; p<0·0001) 28 days post-vaccination, independent of age. VLA1553 was generally safe with an adverse event profile similar to other licensed vaccines and equally well tolerated in younger and older adults.
On June 23rd, 2023, the Advisory Committee on Immunization Practices (ACIP) of the CDC reported that in the US, a CHIKV vaccine it is indeed on the scope (7), and, considering that the Food and Drug Administration (FDA) in November 9th, 2023 has given the VLA1553 vaccine approval for preventing CHIK disease as a travelers’ vaccine (8), Additionally, the European Medicines Agency (EMA) has performed a technical validation of the Marketing Authorization Application (MAA) for Valneva’s single-shot CHIK vaccine candidate VLA1553 and has determined that all essential regulatory elements required for scientific assessment were included in the application. The MAA was granted accelerated assessment by EMA’s Committee for Medicinal Products for Human Use (CHMP) based on the vaccine candidate’s “major interest for public health and therapeutic innovation” (9). Furthermore, as of May/31st/2024, the EMA granted authorization for adults 18 years or older, becoming the first vaccine vs. CHIK ever approved in the European Union (10).
Since nor the World Health Organization (WHO) and the Pan American Health Organization (PAHO) have not yet made any recommendations on CHIK vaccination, our thoughts, despite the hurdles of developing a wide phase 3 Clinical trial, licensure of the first CHIK vaccine (VLA1553) is within reach. However, at first, it may likely only be available for use in adults (18 years or older) in relatively few high-income markets. Nevertheless, before the vaccines is licensed for use in countries where CHIKV is endemic – and where the disease burden is greatest – is further data from extended phase 3 needed?, our guess it is not, however, phase 4 (or effectiveness) studies will be required to establish long-term safety of VLA1553, and to answer critical questions to help health authorities to plan vaccination strategies, such as: should endemic countries include potential CHIK vaccines in routine immunization programs or as an outbreak response vaccine (like in Paraguay)? What volumes of vaccine would be needed in these scenarios? How will sufficient volumes of vaccine be procured? Would the vaccine be included also in children and pregnant women?
In summary, a new milestone has been achieved, and CHIK vaccination is in an early and oncoming horizon, however, several vaccination strategies and safety issues should be performed in order to further establish solid recommendations.
REFERENCES
- Schneider M, Narciso-Abraham M, Hadl S, et al. Safety and immunogenicity of a single-shot live-attenuated chikungunya vaccine: a double-blind, multicentre, randomised, placebo-controlled, phase 3 trial. The Lancet 2023; 401: 2138-47. DOI: https://doi.org/10.1016/S0140-6736(23)00641-4.
- https://www.who.int/news-room/fact-sheets/detail/chikungunya (published 8, December, 2022).
- Silva LA, Dermody TS. Chikungunya virus: epidemiology, replication, disease mechanisms, and prospective intervention strategies. J Clin Invest 2017; 127: 737-49. DOI: 10.1172/JCI84417.
- Torales M, Beeson A, Grau L, et al. Notes from the Field: Chikungunya Outbreak — Paraguay, 2022–2023. MMWR 2023; 72: 636-8. (No DOI available).
- Defining Efficacy of Chikungunya Virus Candidate Vaccines: Different Endpoints Derived From the Virus—Cytokine—Ferritin (VCF) Model. Front. Virol., 23 August 2021 Sec. Antivirals and Vaccines Volume 1 – 2021 | https://doi.org/10.3389/fviro.2021.693439 Stephanie M. Lim1, Sudip K. Dutta and Byron E. E. Martina
- Yoon IK Srikiatkhachorn A, Alera MT, et al. Pre-existing chikungunya virus neutralizing antibodies correlate with risk of symptomatic infection and subclinical seroconversion in a Philippine cohort. Int J Infect Dis 2020; 95: 167-73.
- https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2022-06-22-23/01-02-03-chikungunya-bell-hills-508.pdf. Published 23, June, 2023.
- https://www.fda.gov/news-events/press-announcements/fda-approves-first-vaccine-prevent-disease-caused-chikungunya-virus. Published 9, November, 2023.
- https://valneva.com/press-release/ema-accepts-valnevas-chikungunya-vaccine-marketing-authorization-application-for-accelerated-assessment/. Published 27, November, 2023.
- https://www.ema.europa.eu/en/news/first-vaccine-protect-adults-chikungunya#:~:text=EMA%20has%20recommended%20granting%20a,given%20as%20a%20single%20dose.. Published 31, May, 2024.