Breakthrough Clinical Results
The European Medicines Agency (EMA) has temporarily suspended the use of Valneva's chikungunya vaccine, IXCHIQ®, in individuals over 65 due to reports of 17 serious adverse events (SAEs), including two deaths, in elderly patients with underlying conditions. The EMA emphasizes that the causal link between the SAEs and the vaccine hasn't been established and maintains current recommendations for those aged 12-64. This follows similar precautionary measures taken by the U.S. CDC and French authorities. Valneva is cooperating with health authorities and investigating the SAEs while maintaining confidence in the vaccine's overall risk-benefit profile for most individuals.
Key Highlights
- EMA suspended IXCHIQ® for individuals over 65 due to serious adverse events.
- 17 SAEs, including two deaths, reported in elderly patients with underlying conditions.
- EMA continues to recommend IXCHIQ® for individuals aged 12-64.
- Valneva is cooperating with health authorities and investigating the adverse events.
Incidence and Prevalence
Chikungunya Burden Estimates:
Based on available data from a systematic review of published literature and surveillance records, Chikungunya virus (CHIKV) caused an estimated average yearly loss of over 106,000 disability-adjusted life years (DALYs) globally between 2010 and 2019. This study, registered with PROSPERO (CRD42020192502), reviewed 7,877 studies, screened 916 in detail, and included 21 in the final analysis. It's important to note that these estimates are not currently included in Global Burden of Disease (GBD) reports.
Regional Disparities:
The Americas experienced a substantially higher burden of CHIKV compared to other World Health Organization (WHO) regions. This disparity is likely attributed to a combination of factors:
- Limited active surveillance reporting in other regions, potentially underestimating the true burden.
- Lack of pre-existing immunity in the Americas, making populations more susceptible to severe outbreaks during the study period.
Disease Components:
- Long-term rheumatic sequelae constituted the largest component of the DALY burden associated with CHIKV.
- Acute symptoms and early mortality contributed relatively less to the overall burden.
Data Limitations:
The study acknowledges limitations in accurately determining the true global burden of CHIKV:
- Suboptimal reporting and inconsistent diagnostics affect the precision of incidence estimates and the frequency of complications.
Co-infection with Dengue:
A separate systematic review and meta-analysis (PROSPERO CRD42020175344) examined the prevalence of dengue and chikungunya co-infection. This study, encompassing 83 studies and 43,341 participants, found a pooled global prevalence of 2.5% (95% CI: 1.8-3.4) for co-infection. Asia exhibited the highest prevalence (3.3%, 95% CI: 2.3-4.6), while North America had the lowest (0.8%, 95% CI: 0.3-2.4). Significant variations in co-infection prevalence were observed between countries.
Clinical Presentation and Treatment:
Chikungunya is a zoonotic disease transmitted by infected Aedes spp mosquitoes. After a 1-12 day incubation period, symptoms resembling other febrile infections emerge, including:
- Sudden onset of high fever
- Nausea
- Polyarthralgia (joint pain)
- Myalgia (muscle pain)
- Widespread skin rash
- Conjunctivitis
Serious complications can occur, such as myocarditis, uveitis, retinitis, hepatitis, acute renal disease, severe bullous lesions, meningoencephalitis, Guillain-Barré syndrome, myelitis, and cranial nerve palsies. Treatment is primarily supportive, as there is no specific antiviral therapy or effective vaccine currently available.
Risk Factors and Comorbidities
Risk Factors for Chikungunya Infection (Symptomatic and Asymptomatic):
- Environmental conditions: The presence of garbage piles nearby and spending a significant amount of time outdoors (at least eight hours per day) were identified as risk factors for both symptomatic and asymptomatic chikungunya infection. This suggests that environmental factors play a crucial role in virus transmission and exposure.
Risk Factors for Symptomatic Chikungunya Infection:
- Age: Older age (more than 58 years) was found to be a protective factor against developing symptomatic chikungunya infection. This indicates that younger individuals might be more susceptible to experiencing symptoms upon infection.
- Education: Higher levels of formal education were associated with a reduced risk of symptomatic chikungunya. This suggests a potential link between socioeconomic factors, access to information and resources, and the likelihood of developing symptoms.
Comorbidities and Risk Factors for Severe/Fatal Chikungunya:
- Advanced age: Advanced age was consistently identified as a strong independent risk factor for severe chikungunya and mortality. The odds ratio for death associated with advanced age was reported as 7.35 (p<0.0001) in one study and as high as 19.49 (95% CI 1.98-191.88) in another. This highlights the increased vulnerability of older individuals to severe outcomes.
- Male gender: Male gender was found to be an independent risk factor for death in chikungunya, with an odds ratio of 2.05 (p<0.0001) in one study and 2.07 (95% CI 1.71-2.51) in another. This indicates a potential sex-specific difference in disease severity and outcomes.
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Chronic diseases: Several chronic diseases were identified as significant risk factors for severe/fatal chikungunya:
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Hypertension: Odds ratios for death associated with hypertension ranged from 3.10 (95% CI 2.02-4.77) to 3.74 (p<0.0001).
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Diabetes mellitus: Odds ratios for death associated with diabetes ranged from 2.86 (95% CI 1.75-4.69) to 3.29 (p<0.0001).
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Chronic kidney disease: Odds ratio for death associated with chronic kidney disease was 3.14 (p<0.0001) in one study and 5.81 (95% CI 1.30-25.99) in another.
- Vomiting: Vomiting was identified as a sign of severity and an independent risk factor for death, with an odds ratio of 2.19 (p<0.0001) in one study and 2.18 (95% CI 1.75-2.73) in another.
- Underlying osteoarthritis: The presence of underlying osteoarthritis was found to be a predictor of non-recovery from chikungunya-related rheumatic symptoms, with an odds ratio of 2.9 (95% CI 1.1-7.4).
- Severe initial joint pain: Severe initial joint pain was also a predictor of non-recovery, with an odds ratio of 4.8 (95% CI 1.9-12.1).
It is important to note that the studies included in this analysis varied in their methodologies, populations, and reporting of risk factors and comorbidities. Therefore, the reported odds ratios and prevalence should be interpreted with caution. Further research is needed to confirm these findings and to better understand the complex interplay of risk factors and comorbidities in chikungunya infection.
Drug used in other indications
IXCHIQ® (VLA1553) is currently not being trialled for any other indications besides Chikungunya. It is specifically designed and approved for the prevention of Chikungunya disease in adults.
While the provided texts mention other Chikungunya vaccine candidates and their potential for cross-protection against other alphaviruses (like O'nyong-nyong virus, Mayaro virus, and Ross River virus), these are distinct from trials investigating new indications for IXCHIQ® itself. The research focuses on the breadth of the immune response generated by the vaccine, not on its therapeutic application for other diseases.
The provided texts also discuss various vaccine platforms and approaches used for other diseases, but these are presented in the context of general vaccine development or as background information for Chikungunya vaccine research. They do not indicate that IXCHIQ® is being repurposed or tested for these other conditions.
Therefore, based on the provided information, IXCHIQ® is solely focused on Chikungunya prevention, and there are no ongoing trials exploring its use for other indications.