Single-Dose Dengue Vaccine Effective, Regardless of Baseline Serostatus

One dose of the live, attenuated, tetravalent dengue vaccine Butantan-DV prevented symptomatic disease through 2-year follow-up, regardless of baseline serostatus, a phase III, placebo-controlled study in Brazil found.

Overall, the vaccine was nearly 80% effective in preventing symptomatic dengue during the follow-up period. Among participants with no previous dengue exposure, the vaccine had an efficacy of 73.6% (95% CI 57.6-83.7) when compared with placebo. In those with a history of exposure, the vaccine had an efficacy of 89.2% (95% CI 77.6-95.6), Fernanda Castro Boulos, MD, from the Instituto Butantan in Sao Paulo, Brazil, and colleagues reported in the New England Journal of Medicine.

Butantan-DV consists of full-length attenuated DENV-1, DENV-3, and DENV-4 viruses, plus a chimeric virus targeting both DENV-2 and DENV-4.

The vaccine had an efficacy rate of 89.5% against DENV-1 and 69.6% against DENV-2 serotypes. An important limitation of the study was that no cases of DENV-3 and DENV-4 were observed during the study follow-up.

“An unmet need remains for a dengue vaccine that offers protection from a single dose across a wide age range, regardless of dengue serostatus at baseline,” the authors wrote.

According to the World Health Organization (WHO), the global incidence of dengue infections has reached historic highs since the beginning of 2023 and is spreading into regions previously unaffected by the disease. In the U.S., dengue is most common in Puerto Rico, the U.S. Virgin Islands, and the American Samoa. Cases in the continental U.S. are most often related to travel to endemic areas but local outbreaks have occurred, most recently in Florida.

Initial infection with any dengue serotype is usually mild and provides lifelong protection against reinfection with the same serotype. However, due to antibody-dependent enhancement, second infections often result in severe symptomatic illness that can result in hospitalization and death. After a second infection, cases are usually less severe.

“Nearly 50 years have passed since development of a tetravalent dengue vaccine was initiated at the Walter Reed Army Institute of Research,” wrote Scott Halstead, MD, from the International Vaccine Institute in Seoul, South Korea, in an accompanying editorial.

He noted that the WHO Strategic Advisory Group of Experts on Immunization has recommended that persons age 9 years and older with evidence of at least one previous DENV infection receive three doses of the Dengue vaccine CYD-TDV (Dengvaxia). The group is also considering recommending that children and teenagers in countries where DENV is highly endemic receive two doses of TAK-003, which is not approved in the U.S.

However, during the development of the live, attenuated three-dose CYD-TDV vaccine, people with no history of dengue infection had an increased risk of severe dengue after receiving the vaccine.

And in clinical trials of the DENV-2-derived TAK-003 vaccine, researchers found higher frequency of hospitalization for DENV-3 disease among vaccine recipients who were seronegative at baseline. This vaccine had been under regulatory review by the FDA until manufacturer Takeda voluntarily withdrew the application last July.

“Three fundamental discoveries have challenged the design of a dengue vaccine: antibody-dependent enhancement, the protective role of cellular immunity, and the direct pathogenicity of dengue nonstructural protein 1 (NS1),” Halstead noted.

Further complicating the issue is that the dengue virus shares structural similarities with other flaviviruses, such as the Zika virus, which behaves antigenically like a fifth dengue serotype, he explained. This may result in either protection or pathogenic cross reactivity.

The current study enrolled patients from 2016 to 2019, when Zika infections reached epidemic proportions in Brazil. However, in 2017 and 2018, there was an 80% reduction in total dengue cases and deaths, the editorialist pointed out, possibly due to cross-reactivity of the two flaviviruses.

Halstead noted that none of the trial participants that received a single dose of the Butantan-DV vaccine became severely ill or were hospitalized. “This is in stark contrast to the frequency of severe dengue or hospitalization of vaccinees and controls in clinical trials of Dengvaxia and TAK-003,” Halstead explained. He advised that dengue vaccine clinical trials need to identify how Zika infections affect baseline dengue antibody patterns, risk of severe dengue disease, and vaccine response.

The Butantan-DV vaccine trial had 10,259 healthy volunteers randomized to receive a single vaccine dose and 5,976 randomized to receive a placebo. The primary outcome of the trial was to assess efficacy and short-term safety of the vaccine against symptomatic, virologically confirmed dengue of any serotype, regardless of serostatus at baseline.

By age group, the vaccine efficacy was:

• 80.1% (95% CI 66.0-88.4) among children ages 2 to 6 years
• 77.8% (95% CI 55.6-89.6) among children and adolescents ages 7 to 17 years
• 90% (95% CI 68.2-97.5) among adults ages 18 to 59

Systemic vaccine- or placebo-related adverse events within 21 days after injection occurred more frequently in the group receiving Butantan-DV than in the placebo group (58.3% vs 45.6%). The most common systemic adverse events in the vaccine group were headache, fatigue, and rash.

Serious adverse events within 21 days after vaccine injection were rare in both the vaccine and placebo groups (less than 0.10% for both groups). Over the 2-year follow-up, nine people died in the vaccine group and seven died in the placebo group. None of the deaths were determined to be caused by dengue or the vaccine.

“Given the realities of the dimensions of the dengue pandemic in the 20th and 21st centuries, a highly effective, one-dose, tetravalent vaccine remains in high demand. Butantan-DV clinical trials should continue and, if possible, be expanded,” Halstead urged.