Update on Safety of the dengue vaccine Qdenga®
The WHO position paper on dengue vaccines, updated in May 2024,1noted that no cases of anaphylaxis were observed during a clinical trial of the Takeda dengue vaccine (TAK-003, Qdenga®) conducted in 20 099 participants who were randomly assigned to TAK-003 (n=13 401) or placebo (n=6698). One month after its introduction in Brazil in 2023, however, 16 cases were reported (4.4 per 100 000 doses administered). The position paper noted that the currently approved package insert for Qdenga® includes precautionary measures to mitigate the risk of anaphylaxis. A full assessment of the cases in the Brazilian national immunization programme is under way
On 9 February 2024, a public mass vaccination campaign for children aged 10–14 years began in priority municipalities in Brazil. The vaccine safety profile has been monitored by the Brazilian general coordination of pharmacovigilance in the national immunization programme (DPNI) from events supposedly attributable to vaccination or immunization (ESAVI), which included clinical and epidemiological investigation of hypersensitivity reactions and anaphylaxis. At the meeting of GACVS in May 2024, DPNI presented an overview of the safety surveillance data on Qdenga® collected to date. At the present meeting, further data from Brazil were presented, up to 12 September 2024, by which time 2 164 503 first vaccine doses and 714 298 second vaccine doses had been administered in the public and private sectors.
Between 1 March 2023 and 12 September 2024, 501 hypersensitivity reactions (147.1 per million doses) were reported after vaccination with Qdenga®. Of these, 447 occurred after the first dose (183.1 per million doses) and 24 after the second dose (31.0 per million doses). Of all reactions, 124 were classified as anaphylaxis (36.4 per million doses), with 117 after the first dose (44.5 per million doses) and 7 after the second dose (9.0 per million doses).
During the investigation, the diagnosis of all cases was validated according to the World Allergy Organization (WAO) and the revised Brighton Collaboration standardized case definition2 (76 cases confirmed according to WAO, 84 according to the Brighton Collaboration case definition and 50 according to both). The median time between vaccine administration and onset of anaphylaxis was 25 min (ranging from 3 to 360 minutes); there was no pattern by sociodemographic variables. A small case–control study in Rio de Janeiro and Federal District found no statistically significant association between anaphylaxis after Qdenga® administration and possible risk factors, including concomitant vaccination, anaphylaxis with any previous vaccine, history of allergies, previous arbovirus infection, chronic disease or use of medication at the time of vaccination. The Brazil Ministry of Health considers that the benefits of vaccination outweigh the risks, provided local services ensure safe practices. Currently, immunization outreach activities are being replaced by in-facility vaccination.
Invited speakers from Brazil described a clinical case series of 11 children with post-vaccination hypersensitivity and anaphylaxis at the Hospital das Clínicas, São Paulo. Two had a positive intradermal test. For children with mild-to-moderate reactions, a supervised second dose was advised, while a second dose was contraindicated for those with confirmed anaphylaxis. A research project is under way to investigate risk factors, including possible allergic components of the vaccine and the mechanisms of the reactions.
Another frequently reported AEFI is dengue-like symptoms including dengue fever, which prompted development of diagnostic tests and guidelines to distinguish between wild-type virus infection and vaccine-related viraemia. Five suspected dengue cases after vaccination were reported, and DENV-2, DENV-3 and DENV-4 strains were detected in blood samples. One case in an 87-year-old resulted in death, while the others, in 3 males and 1 female aged 7–42 years, were not serious. Three cases were confirmed as DENV-2 and one as DENV-4.3
Other observed risks include potential vaccine-associated enhanced disease (VAED) and reactivation of virulence in immunocompromised individuals. There is a gap in knowledge about use of vaccine during pregnancy or lactation. A representative of the Pan American Health Organization mentioned that a phase-4 study was planned in Brazil to assess the effectiveness and safety of Qdenga® booster doses.
The Committees recommended ongoing monitoring of anaphylaxis, hypersensitivity events and other AEFIs following use of Qdenga® vaccine in Brazil and other regions. It also called for continued support, including commitment of the vaccine manufacturer for immunological studies to identify vaccine triggers, explore mechanisms of mast cell and basophil degranulation and identify risk factors and serological, cellular or genetic markers.
The Committees suggested that clear communication of risks to parents and vaccinees, training for vaccine and health-care providers in managing anaphylaxis and reporting of adverse events to the global database VigiBase be implemented. The National Immunization Technical Advisory Group and the Regional Immunization Technical Advisory Group should assess harm versus benefit when making vaccine recommendations.
It was also suggested that the post-vaccination observation period be extended to identify and treat potential cases of anaphylaxis appropriately in vaccination facilities.
The Brazilian national regulatory authorities were encouraged to work with the manufacturer to review the risk assessment of this signal and the aspects of the vaccine’s manufacture that could affect its composition and allergenicity.
The Committees emphasized the importance of monitoring the clinical and epidemiological characteristics of dengue infections in vaccinated populations to address the risk of VAED and to explore its mechanisms. The Committees recommended that vaccination data be integrated into arboviral surveillance systems and that full clinical details of severe dengue cases and deaths among vaccinated individuals be provided. In view of the complexity of diagnosing and monitoring this condition, the Committees suggested that experts in arboviral diseases, virology and immunology be involved to guide discussions and provide informed recommendations. To address potential dengue due to reactivated vaccine virus, monitoring of cases and deaths due to severe dengue within 30 days of vaccination should include diagnosis to differentiate between vaccine and wild virus viraemia. Comprehensive AEFI/ESAVI reporting and case investigations should be integrated into national and global safety surveillance systems.
1 No. 18, 2024, pp. 203–224
2 Gold MS. (2022) Anaphylaxis: Revision of the Brighton collaboration case definition. Vaccine. 2022;41(15):2605–14. https://doi.org/ 10.1016/j.vaccine.2022.11.027.
3 de Oliveira RD et al. A case report on symptomatic disease caused by serotype 4 vaccine virus following tetravalent anti-dengue vaccination. Travel Med Infect Dis. 2024;62:102782. https://doi.org/10.1016/j.tmaid.2024.102782.
Safety of the dengue vaccine Qdenga®
Extract from report of GACVS meeting of 15-17 May 2024, published in the WHO Weekly Epidemiological Record on 9 August 2024
The WHO position paper on dengue vaccines, updated in May 2024,1 noted that, although no cases of anaphylaxis were observed during a clinical trial of the Takeda dengue vaccine (TAK-003; Qdenga®), 16 cases were reported after its introduction in Brazil in 2023 (4.4 per 100 000 doses administered). The paper noted that the currently approved package insert for Qdenga® includes precautionary measures to mitigate the risk of anaphylaxis, that an update that will include anaphylaxis as an adverse reaction has been initiated, and that a full assessment of the cases in the Brazilian national immunization programme is under way. Post-marketing safety data on this vaccine were reviewed, with emphasis on new data from Brazil.
The Brazilian General Coordination of Pharmacovigilance in the national immunization programme (DPNI) presented an overview of introduction of Qdenga® and the adverse events. Qdenga® was first used in Brazil in private health services from mid-2023. On 9 February 2024, a public mass vaccination programme for children aged 10–14 years began in priority municipalities. The DPNI then investigated in detail the clinical and epidemiological events supposedly attributable to vaccination or immunization (ESAVIs), which included hypersensitivity reactions, including anaphylaxis, in data collected through the National Surveillance System.
During the study period (1 March 2023 to 3 May 2024), over 1.4 million doses of the vaccine were administered, and 74 cases of serious non-fatal ESAVIs were reported after administration of the vaccine. Of these, 43 were diagnosed as anaphylaxis (3.3 cases per 100 000 doses administered), of which 4 cases were anaphylactic shock (0.3 cases per 100 000 doses administered). No fatal ESAVIs were reported. The higher-than-expected rate of anaphylaxis prompted investigations into the possible causes of this safety signal, recommendations for precautionary and prevention measures, and communication of the risk to the public. Despite the disproportionate number of hypersensitivity reactions compared to other vaccines and anaphylaxis reported after exposure to Qdenga®, the Ministry of Health maintains its recommendation for use of this vaccine.
In November 2023, the Pan American Health Organization (PAHO) Technical Advisory Group on Immunization supported use of Qdenga® in children aged 6–16 years living in settings with a high disease burden and a high transmission intensity and recommended that pilot introduction of the vaccine be considered, accompanied by a robust phase-4 post-marketing study.2 A representative of PAHO described to GACVS the risks and knowledge gaps identified in relation to introduction of Qdenga® in the Region of the Americas, challenges for safety surveillance and recommendations to countries in the Region on safety surveillance through a guidance document.
Since identification of the anaphylaxis safety signal, PAHO has also been working with countries to evaluate the risk of anaphylaxis and anaphylactic shock after administration of the vaccine. For surveillance of vaccine-associated enhanced disease (VAED), PAHO is developing recommendations for harmonizing surveillance of arbovirus ESAVIs, an algorithm for diagnosis of dengue in vaccinated people, and guidance on investigation of severe dengue cases. PAHO has made several recommendations to address other knowledge gaps in the safety of this vaccine, which include ESAVI monitoring and signal detection in pregnant and lactating women, including identification and follow-up of inadvertent vaccination in passive surveillance systems.
GACVS congratulated Brazil on its comprehensive AEFI monitoring and vaccine safety plan, and management of anaphylaxis cases after Qdenga® administration. The cases of anaphylaxis reported appear to fulfil the strict case definition, although further work is required to understand the potential biological or other mechanisms involved. The Committee noted that the activities being undertaken by PAHO in the Region of the Americas are relevant to other countries and regions that are considering introduction of this vaccine. The manufacturer, Takeda, has reported only 2 other cases of anaphylaxis globally in response to the millions of doses distributed, which occurred in Argentina and Thailand. The Committee emphasized the importance of including the risk of anaphylaxis in the vaccine product information. GACVS recommended that, as for other vaccines, all countries that introduce Qdenga® should have protocols, resources and training for the management and investigation of anaphylaxis after immunization, including the availability and use of adrenaline where appropriate. Further, countries that introduce this vaccine could consider conducting studies to assess the rate of anaphylaxis in their AEFI surveillance systems or by other methods. The GACVS emphasized the importance of longer-term surveillance for potential VAED, including harmonization with surveillance for other arboviral products.
1 WHO position paper on dengue vaccines – May 2024. Geneva: World Health Organization; 2024 (https://www.who.int/publications/i/item/who-wer-9918-203-224, accessed 31 May 2024).
2XI Ad Hoc Meeting of the PAHO Technical Advisory Group (TAG) on Vaccine-Preventable Diseases, 21 November 2023. Washington DC: Pan American Health Organization; 2024 (https://iris.paho.org/handle/10665.2/59314, accessed May 2024).
Safety of the TAK-003 dengue vaccine
Extract from report of GACVS meeting of 15-16 May 2023, published in the WHO Weekly Epidemiological Record on 11 August 2023
SAGE requested GACVS to review the clinical trial safety data for the TAK-003 live attenuated dengue vaccine, manufactured by Takeda Pharmaceuticals. SAGE provided the context of known complexities in dengue vaccine safety, as observed with the CYD-TDV vaccine (Dengvaxia). The TAK-003 vaccine, like CYD-TDV, is based on chimeric constructs though with different backgrounds, YF 17D virus in the case of CYD-TDV versus an attenuated dengue 2 virus in the case of TAK-003. While it was considered biologically plausible that similar safety concerns could be observed, it was also noted that dengue 2 backbone of TAK-003 induces a broader range of dengue specific responses than seen with CYD-TDV.
Representatives from Takeda Pharmaceuticals were invited to present data from pre-licensure trials, followed by confidential presentations from 2 independent experts on B-cell and T-cell immune responses to the dengue virus and vaccines.
The Committee conveyed to SAGE its views on the TAK-003 vaccine and the current information gaps relating to vaccine safety. The Committee expressed interest in continuing to review any additional emerging data. The SAGE recommendations and deliberations concerning the TAK-003 vaccine will be published when available.
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