Breakthrough Clinical Results
Valneva announced that the FDA and CDC recommend pausing the use of their chikungunya vaccine, IXCHIQ®, in elderly individuals due to reported serious adverse events. The agencies are investigating these events, which mostly occurred in elderly individuals with underlying conditions. The vaccine remains recommended for individuals aged 18-60 (FDA/CDC) and 12-64 (EMA).
Key Highlights
- FDA and CDC recommend pausing IXCHIQ® use in elderly individuals due to reported serious adverse events (SAEs).
- Ongoing investigations into SAEs are underway.
- IXCHIQ® remains recommended for individuals aged 18-60 years (FDA/CDC) and 12-64 years (EMA).
- Valneva is cooperating with health authorities and will provide updates as investigations conclude.
Incidence and Prevalence
Global Incidence and Prevalence of Chikungunya:
Several studies provide insights into the incidence and prevalence of chikungunya, highlighting its global impact and the challenges in obtaining precise estimates due to variations in reporting and methodologies.
Incidence:
A systematic review and modelling study published in 2023 estimated the global long-term median annual force of infection (FOI) for chikungunya to be 0.007 (95% UI 0.003-0.010). FOI represents the rate at which susceptible individuals acquire chikungunya infection. This study also highlighted the heterogeneity in FOI across different locations, classifying 17 (22%) of 76 locations as endemic and 59 (78%) as epidemic settings. The FOI varied from 0·0001 (0·00004-0·0002) to 0·113 (0·07-0·20) across these locations.
Another systematic review published in 2021 assessed epidemiological trends of chikungunya from 1999 to 2020. This review identified 97 outbreak reports from 45 countries and 50 seroprevalence studies from 31 countries across Africa, Asia, Oceania, the Americas, and Europe. However, the review highlighted substantial gaps in epidemiological knowledge, particularly regarding granular data on disease incidence and age-specific infection rates, as well as the diversity of methodologies used in the studies.
A 2019 study estimated that chikungunya caused an average yearly loss of over 106,000 disability-adjusted life years (DALYs) between 2010 and 2019, with a substantially higher burden in the Americas compared to other WHO regions. This study also noted that long-term rheumatic sequelae contributed the largest DALY component for chikungunya.
Prevalence:
The 2023 systematic review and modelling study estimated the highest median seroprevalence at age 10 years to be in South Asia (8·0% [95% UI 6·5-9·6]), followed by Latin America and the Caribbean (7·8% [4·9-14·6]), with the lowest median seroprevalence in the Middle East (1·0% [0·5-1·9]).
The 2021 systematic review did not provide a pooled prevalence estimate due to the heterogeneity of methodologies used in the included studies. However, it emphasized the need for a better understanding of chikungunya disease dynamics and the duration of long-term population immunity to inform vaccine development efforts.
Challenges and Future Directions:
Obtaining precise estimates of chikungunya incidence and prevalence is challenging due to several factors, including underreporting, inconsistent diagnostics, and the diversity of methodologies used in epidemiological studies. Future research should focus on standardizing surveillance and diagnostic methods, collecting more granular data on incidence and age-specific infection rates, and conducting further seroprevalence studies in underrepresented regions to improve our understanding of the global burden of chikungunya.
Risk Factors and Comorbidities
Chikungunya Risk Factors and Comorbidities:
Chikungunya virus (CHIKV) infection poses a significant public health challenge, particularly due to the risk of severe disease and chronic complications. Several risk factors and comorbidities have been identified that increase the likelihood of adverse outcomes in CHIKV infection. Here are three prominent ones:
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Advanced Age:
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Increased Mortality Risk: Advanced age is consistently identified as a major risk factor for mortality in CHIKV infection. A study of a large epidemic in Brazil found that advanced age significantly increased the odds of death (OR 7.35, p<0.0001). Another study also identified age ≥60 years as a significant risk factor for mortality (OR = 19.49, 95% CI 1.98-191.88).
- Chronic Disease Prevalence: Older individuals often have underlying chronic diseases, which can exacerbate CHIKV infection and contribute to severe outcomes.
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Impaired Immune Response: Age-related decline in immune function may also play a role in increased susceptibility to severe CHIKV infection.
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Comorbidities (Hypertension, Diabetes, Chronic Kidney Disease):
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Hypertension: Several studies have identified hypertension as a significant risk factor for severe CHIKV and increased mortality. One study found hypertension increased the odds of death (OR 3.74, p<0.0001), while another study found it to be a significant mortality risk factor (OR = 3.10, 95% CI 2.02-4.77).
- Diabetes: Diabetes mellitus is another comorbidity associated with severe CHIKV and increased mortality risk. One study found diabetes increased the odds of death (OR 3.29, p<0.0001), while another study found it to be a significant mortality risk factor (OR = 2.86, 95% CI 1.75-4.69). Another study found that severe CHIKV cases had a significantly higher proportion of diabetes than non-severe cases.
- Chronic Kidney Disease: Chronic kidney disease is also associated with increased mortality risk in CHIKV infection. One study found chronic kidney disease increased the odds of death (OR 3.14, p<0.0001), while another study found it to be a significant mortality risk factor (OR = 5.81, 95% CI 1.30-25.99).
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Exacerbated Inflammation: These comorbidities can exacerbate the inflammatory response triggered by CHIKV infection, leading to more severe disease.
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Male Gender:
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Increased Mortality Risk: Male gender has been identified as a risk factor for increased mortality in CHIKV infection. One study found that being male increased the odds of death (OR 2.05, p<0.0001), while another study also found it to be a significant mortality risk factor (OR = 2.07, 95% CI 1.71-2.51).
- Underlying Biological Mechanisms: The reasons for increased risk in males are not fully understood, but may relate to underlying biological differences in immune responses or hormonal factors.
Other Risk Factors and Comorbidities:
While the above three are prominent, other factors and conditions can also influence CHIKV infection outcomes. These include:
- Low Educational Level: Associated with higher mortality risk in some studies.
- Leukopenia and Vomiting: Can be signs of severity.
- Obesity: May contribute to severe outcomes.
- Cardiac Diseases and Asthma: May increase risk of complications.
It's important to note that the presence of these risk factors and comorbidities does not guarantee severe CHIKV infection, but rather increases the likelihood. Early diagnosis, supportive care, and management of comorbidities are crucial for improving outcomes in CHIKV infection.
Drug used in other indications
IXCHIQ® (VLA1553) is currently not being trialed for any other indications besides Chikungunya. It was specifically developed and approved for the prevention of Chikungunya disease in adults.
While some research explores the potential of IXCHIQ to offer cross-protection against other related alphaviruses like O'nyong-nyong virus (ONNV), Mayaro virus (MAYV), and Ross River virus (RRV), these are not separate clinical trials for new indications. One study examined the cross-neutralizing antibody responses elicited by IXCHIQ against these viruses. The results suggested that the vaccine does induce cross-nAbs, with potency decreasing as the genetic distance from CHIKV increases. This cross-protection is a characteristic of the vaccine's immune response, not a separate indication.
Clinical trials for IXCHIQ have focused on its safety and efficacy against Chikungunya. These trials have included:
- Phase 1 dose-finding trial: To determine the appropriate vaccine dose.
- Pivotal Phase 3 trial: To evaluate the immunogenicity of the vaccine and establish a surrogate marker of protection.
- Phase 3 lot-to-lot consistency trial: To ensure consistent vaccine production quality.
- Post-licensure studies: Ongoing and planned studies to confirm clinical efficacy/effectiveness and safety in various populations, including younger individuals and those in endemic countries.
These trials have primarily used a single intramuscular dose of VLA1553 and evaluated outcomes such as seroconversion rates, neutralizing antibody titers, and adverse events. The trials have not explored the use of IXCHIQ for other diseases.
It's important to note that while cross-protection against other alphaviruses is a potential benefit of IXCHIQ, it is not currently being actively pursued as a separate indication in clinical trials. The focus remains on its use for preventing Chikungunya.