Summary

Name:

Dengvaxia«

Synonyms:

ChimeriVax-Dengue; ChimeriVax Dengue; CYD Dengue; CYD-TDV; CYD TDV

Sponsor:

Sanofi Pasteur / Sanofi Aventis (global presence)

Co-Sponsor:

Acambis (acquired by Sanofi Pasteur; global presence)

Type of product:

Vaccine

Viral family:

Flaviviridae

Status:

Market
Approved for market in Mexico (Dec. 2015), Philippines (Dec. 2015), Brazil (Dec. 2015), Salvador (Jan. 2016); Filings for marketing authorization completed in several countries endemic for Dengue Fever virus; Recommended for approval by CHMP Committee o

Dengvaxia« 

Synonyms:ChimeriVax-Dengue; ChimeriVax Dengue; CYD Dengue; CYD-TDV; CYD TDV       Sponsor:Sanofi Pasteur / Sanofi Aventis (global presence)       Co-Sponsor:Acambis (acquired by Sanofi Pasteur; global presence)       Type of product:Vaccine       Mode of action:Recombinant, viral expr vector       Viral family:Flaviviridae       Virus:Dengue virus      

Details

Characteristics:
Live attenuated tetravalent vaccine for prevention of Dengue virus infection (all four serotypes DEN-1 to DEN-4);

Composed of four live recombinant, attenuated vaccines (CYD-1–4) based on a well-characterized Yellow Fever virus strain 17D (YFV 17D) genomic backbone modified to express the pre-membrane and envelope genes of one of the four Dengue virus serotypes;
Produced in vitro using Vero cells without serum;

Vaccine is genetically and phenotypically stable, non-hepatotropic, and less neurovirulent than YFV 17D vaccine;
Hybrid virions composing the vaccine are unable to infect mosquitoes by oral route;
Vaccine elicits stimulation of human dendritic cells and induces significant immune responses in monkeys
 
Ref.: Brandler et al., Am J Trop Med Hyg. 2005 Jan;72(1):74-81 ( www.ncbi.nlm.nih.gov/pubmed/15728870 ); Deauvieau et al., Am J Trop Med Hyg. 2007 Jan;76(1):144-54 ( www.ncbi.nlm.nih.gov/pubmed/17255244 )
PK Data, Dosage or Route of Administration:

Administration by injection

In vivo and clinical data:
Phase I trial done with only DEN-2 viral serotype showed induction of neutralising antibodies in over 95% of vaccinees to homologous vaccine strain or to wild-type Dengue Virus serotype 2;
  
Phase I of tetravalent vaccine, completed in 2005, confirmed high-level seroconversion;
 
Phase II results were presented at Sanofi Pasteur Research & Development Meeting on Sept. 17, 2007, and at 56th Annual Meeting of the American Society of Tropical Medicine and Hygiene (ASTMH), Philadelphia, PA, in Nov. 2007:
  • Immunization with tetravalent vaccine induced seroneutralizing antibody response against all 4 serotypes of Dengue virus in 100% of US trial participants
  • No SAEs were reported

 

Results published in early 2010 (Morrison et al., J Infect Dis. 2010 Feb 1;201(3):370-7) www.ncbi.nlm.nih.gov/pubmed/20059357 ) showed that all participants seroconverted against all 4 serotypes after receiving 3 doses at 0, 4, and 12-15-months, and almost all seroconverted after 2 doses given 8-11 months apart; No SAEs related to vaccine were reported;

 

Results of Phase III trial NCT01373281 were published by Capeding et al. (Lancet. 2014 Oct 11;384(9951):1358-65) ( www.ncbi.nlm.nih.gov/pubmed/25018116 ):

  • Phase III trial NCT01373281 was an observer-masked, randomized, controlled, multicentre study conducted in Indonesia, Malaysia, Philippines, Thailand, Vietnam, in which 10275 children aged 2-14 years were randomly assigned (2:1) to receive 3 injections of CYD-TDV tetravalent Dengue vaccine (N=6851) or placebo (N=3424), at months 0, 6, and 12, with follow-up until month 25
  • Primary objective was to assess protective efficacy against symptomatic, virologically confirmed Dengue virus infection, irrespective of disease severity or serotype, that took place more than 28 days after 3rd injection; Primary endpoint was for the lower bound of the 95% CI of vaccine efficacy to be greater than 25%, with data analyzed according to intention to treat and per procotol
  • For primary analysis, 98% of children in both vaccine group and placebo group were included
  • 250 cases of virologically confirmed Dengue virus infection took place more than 28 days after 3rd injection: 117 in vaccine group and 133 in placebo group, giving a vaccine efficacy of 56.5% (95% CI 43.8–66.4), meeting primary endpoint
  • 647 SAEs were observed: 402 in vaccine group and 245 in placebo group; 54 (1%) children in vaccine group and 33 (1%) of those in placebo group had SAEs that happened within 28 days of vaccination; SAEs were consistent with medical disorders in this age group and were mainly infections and injuries
  • Overall, data showed vaccine efficacy and safety in this group age

Development status

Market
Approved for market in Mexico (Dec. 2015), Philippines (Dec. 2015), Brazil (Dec. 2015), Salvador (Jan. 2016); Filings for marketing authorization completed in several countries endemic for Dengue Fever virus; Recommended for approval by CHMP Committee o

Remarks

Recombinant vaccine for Dengue Virus;
 
Acambis designed and performed initial vaccine development, starting with individual vaccines;
Acambis also completed Phase I trials;
 

Sanofi Pasteur acquired exclusive rights on vaccine and assumed further development of vaccine;

 

Phase II pediatric trial (healthy children 4 to 11 years old) done in Thailand (Province of Ratchaburi), with collaboration from Mahidol University of Thailand, Ministry of Public Health of Thailand, and Pediatric Dengue Vaccine Initiative (PDVI);

Multicenter Phase II study done in Mexico, Colombia, Honduras, Puerto Rico, Peru, Vietnam, Philippines, Singapore, Thailand;

 

Multicenter Phase III studies done in Indonesia, Malaysia, Philippines, Thailand, Vietnam, Australia;

 

On Dec. 9, 2015, Sanofi Pasteur announced that The Federal Commission for the Protection against Sanitary Risks (COFEPRIS) have granted marketing authorization to Dengvaxia® for the Mexican market;
This represents the first market approbation for this vaccine globally;
Dengvaxia® has been approved for prevention of Dengue virus disease in preadolescents, adolescents and adults, 9 to 45 years of age living in endemic areas;

Marketing authorization was also granted by Philippines in Dec. 2015;

 

On Dec. 28, 2015, Sanofi Pasteur announced that Brazilian regulatory authorities (ANVISA) have granted approval to Dengvaxia® for the prevention of disease caused by all four viral Dengue types in individuals from 9-45 years of age living in endemic areas;

 

In Nov. 2017, Sanofi released findings from a long-term data analysis, which suggested that in Dengue-naive pts, the vaccine can induce a phenomenon known as antibody-dependent enhancement of Dengue infection, in which Dengue-primed individuals seem to be at greater risk for developing severe disease after a second, heterologous Dengue infection (Ferguson et al., Science 2016;353:1033-6);
Therefore, in at least some of these people, the vaccine appears to mimic the natural infection but without making recipients sick;
On the other hand, analyses of long-term clinical data confirmed the ability of the vaccine to provide persistent protective benefit against Dengue fever in people who had prior infection;

As a consequence of these findings, the Philippines government halted its mass Dengue vaccination program in Nov. 2017, after more than 800,000 children had been vaccinated;
Sanofi asked Philippines health authorities (and other countries where the vaccine is approved) to change the vaccine’s label to reflect the risk for Dengue-na´ve individuals, generating a controversy still raging in Jan. 2018 (FiercePharma Jan. 2018);

 

An expert panel from the University of the Philippines-Philippine General Hospital (UP-PGH) released findings in early Feb. 2018 from an investigation on the deaths of 14 children who received the vaccine; According to the panel, a causal association was suspected in three cases, two of which could have been associated with vaccine failure, although further testing of tissue samples and antibodies was deemed necessary before making final conclusions