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NEW ORLEANS – New data on several new dengue vaccines have been reported. They all show that the safety and immunogenicity are satisfactory and hopefully that they will be able to avoid the problems affecting the controversial Dengvaxia product of Sanofi-Pasteur.
In a series of presentations at the annual meeting of the ASTMH (American Society of Tropical Medicine and Hygiene), researchers presented the results of four different vaccine-based vaccines based on modified dengue, all designed to elicit an immune response to the four major serotypes of dengue.
Some of the data included the results of provocation studies showing protection against viral diseases. But since they were conducted with relatively unreliable laboratory viruses, and not wild-type strains, it will take some time before commercialization is considered.
As one researcher said in describing the progress of her group, but could apply to everyone: "We still have work to do, but it's encouraging."
TV003 and TV005
Anna Durbin, MD, of the Bloomberg School of Public Health at Johns Hopkins University in Baltimore, first discussed the results with a tetravalent vaccine called TV003, which has been in development for several years. It includes three attenuated dengue viruses (paralyzed by the removal of key sections of its genome), one of which is further designed to include immunogenic proteins of the fourth serotype.
In the current US study, 60 volunteers were randomized 2: 1 to receive single doses of TV003 or placebo, and then 4 weeks later challenged by modified but still infectious versions of dengue fever viruses. Types 2 and 3 (Crisis Emblem The two challenge strains were originally developed as candidate vaccines, with genomic deletions designed to make them non-infectious – yet, after being tested on non-human primates, they have been shown to be totally infectious).
None of the actively vaccinated group members presented with viremia when analyzing blood samples taken 16 days after infection, although one of the subjects infected with the modified strain DENV-2 (5%) developed a rash typical of active dengue fever. In contrast, all placebo group members developed viremia and almost all had dengue rash (rash is also common as a side effect of the anticholengen vaccine – observed in 88% of actively vaccinated participants). – but they usually differ from typical cases: dengue, with less erythema, for example).
Apart from the vaccine-induced rashes, no adverse events were observed more frequently in vaccine recipients and much less, mainly those associated with dengue, such as fever, headache, myalgia and neutropenia.
Durbin said the trial data was being analyzed to track the time course of immune responses to vaccination.
Another study of a similar agent, TV005, is a bit closer to what would be of most interest to clinicians: it was conducted in Bangladesh, where wild-type dengue is in circulation.
Presented by Mary Claire Walsh, PA-C, from the University of Vermont in Burlington (also involved in the TV003 study), the study conducted in Bangladesh randomized a total of 192 people into four generations (young children, older children, adolescents, adults). , assigned 3: 1 to active vaccine or placebo. TV005 includes attenuated strains of each of the four dengue serotypes; the modified strain of DENV-2 was assayed at 10 times the level of the other three to maximize protection against the corresponding wild-type serotype.
About two-thirds of the adults were already HIV-positive for dengue exposure at baseline; it was less common in younger cohorts (for example, less than 10% in pre-adolescent children).
Post-administration antibody titers showed seroconversion rates for all four serotypes reaching or approaching 100% for vaccinated participants who were seropositive at baseline. For those initially seronegative, the conversion rates were lower but at least 70%.
In addition, in a challenge study involving actively vaccinated adolescent and adult participants, only 4% experienced viremia.
The security data was similar to that of the TV003 study, leading Walsh to conclude that TV005 was "safe and well tolerated".
GSK Program
Michael Koren, MD, of the Walter Reed Army Research Institute in Washington, presented the three-year results of several candidate vaccines developed by GlaxoSmithKline (GSK). These involved inactivated (as opposed to attenuated) dengue viruses administered with adjuvants, including alum or proprietary compounds (ASO1E or ASO3B).
The study was conducted in Puerto Rico, another area where dengue fever is common. A total of 100 adults were randomized into groups of 20 to four GSK vaccine formulations or placebo. About 80% of each group were successfully followed for a blood test and a potential dengue infection for the full 3 years.
During this period, nine participants developed symptoms of possible dengue infection (13 episodes in total), but molecular analyzes revealed the active presence of dengue fever in no dengue fever. between them. Koren spoke a little about three cases in which titers of anti-dengue antibodies increased during these episodes: two of them involved placebo recipients and, in all three cases, treating clinicians determined that individuals had minor bacterial infections.
Koren also reported average antibody titres frequently tracked during follow – up, which showed decreasing levels over time, which still remained well above baseline levels.
What about dengvaxie?
These presentations danced around the elephant in the room. Serious side effects associated with Sanofi-Pasteur's dengvaxia resulted in the discontinuation of some vaccination programs and the modification of the product's label earlier this year. To be fair, only the TV005 study included children and was too small for the effect to be treated.
But a presentation by Daniel Laydon, PhD, of Imperial College London, who had collaborated with Sanofi-Pasteur researchers in a modeling study, directly addressed the issue.
Specifically, the problem was that young children who had never been exposed to dengue presented an increased risk, rather than a reduced risk, of contracting severe dengue infections and hospitalizations after vaccination. In the Philippines, several children died, causing a rage earlier this year. Sanofi-Pasteur responded by informing providers that the serologic status of dengue fever in young children should be checked before giving the vaccine and that it should not be administered to those whose test is negative.
In the background, Laydon explained what now seems to be the underlying mechanism for this seemingly paradoxical effect, given that vaccines are supposed to prevent or lessen infections and not make them worse. Unlike most infections, the initial effects of dengue fever on people are usually mild to moderate. Second infections are significantly more likely to be serious; Subsequent exposures then produce only mild effects, probably because the person then developed a strong protective immune response.
In people without prior exposure, vaccination acts as an initial wild-type infection (hence the vaccine-associated rash, for example). When the person is then exposed to wild-type dengue, it is essentially a second infection and the risk of developing severe symptoms is then maximum.
We still do not know why only young children seem to run a major risk. However, the Bayesian modeling study reported by Laydon suggested that the problem was already identifiable (if not actually identified) in the Phase III vaccine trial data. The model developed by the group consisted of two components: one that treated vaccination as a "silent" initial infection (thus changing the course of subsequent exposures to dengue) and the other that treated the immunity generated by the vaccine as a transient in both extent and duration. The magnitude of immunity is in turn affected by the infective serotype, the initial exposure status, and the age of the patient; The duration also varies according to the serological status and age.
Guided by the Phase III data, the model "predicted" the real situation: the vaccine has a "negative efficacy" in HIV-negative children aged 2 to 16 years.
In addition, says Laydon, "the effect of age is independent of serostatus", although it becomes more visible in the seronegative group.
It remains to be seen whether the other vaccines under development (which also include a Takeda product, TAK-003, currently in phase III) will have the same problem. Dengvaxie is a unique product, based on an attenuated yellow fever virus designed to express dengue proteins and having very variable effects on different serotypes of dengue, while all the others discussed during the session. ASTMH use the dengue virus itself. Time and trial data will tell if it makes a difference.
2018-10-30T18: 15: 00-0400
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