Léo Ramos Chaves / Pesquisa FapespVirologist Dr. Maurício Lacerda Nogueira knows dengue well. For almost 20 years he has been studying the evolution of the virus, which occasionally sparks epidemics in Brazil, leaving hundreds of thousands of people bedbound for days on end. He himself has had dengue fever three times. “It made me feel miserable,” he says.
Born in Jaboticabal, in the interior of São Paulo State, Nogueira has a degree in medicine from the Federal University of Minas Gerais (UFMG), where he also did a master’s degree and a doctorate. In 2004, he settled in São José do Rio Preto, a town in the state of São Paulo where dengue fever and other diseases transmitted by the Aedes aegypti mosquito are endemic.
At the São José do Rio Preto School of Medicine (FAMERP), he established one of the laboratories of the Viral Genetic Diversity Network, funded by FAPESP, and investigated factors behind the development of severe dengue fever and how immunity evolves after infection. More recently, he was head of a center at FAMERP that evaluated the dengue vaccine candidate developed by the Butantan Institute: Butantan-DV.
In an interview given via videocall on January 31, Nogueira spoke about the effectiveness of the various dengue vaccines currently available and drew attention to the risk of the current epidemic being the largest ever experienced in Brazil. Read the highlights below.
A total of 232,000 suspected cases of dengue were recorded in January, 2.5 times the number recorded in January 2023. What should we expect in the coming months?
I expect cases to rise significantly until April. Over the past 20 years, cases have peaked between late March and mid-May. Then they drop sharply with the arrival of the first cold front. It is possible that 2024 could become the year with the highest number of suspected—and probably confirmed—cases in Brazil’s history.
In the first month of this year, there were 15 confirmed deaths from dengue. In January 2023, there were 61. Is dengue less lethal this year?
It’s difficult to know for sure. Dengue behaves differently in Brazil than in Singapore, for example, which is an island. There, epidemics manifest in a more homogeneous way. But in Brazil, we see multiple phenomena occurring at the same time. In Belo Horizonte, there is a strong presence of dengue virus serotypes 1 and 2. In the highly populated state of São Paulo, in addition to dengue serotypes 1 and 2, we see many cases of Chikungunya, which causes similar clinical symptoms to dengue and can make the data a bit less clear. In some parts of the country, the serotype 2 virus in circulation is a cosmopolitan strain, while in São Paulo it is the Asian-American strain. We are also getting reports that serotype 3 is appearing in some places. On top of this complexity is the concern that some states in the Northeast that have historically been heavily affected by dengue are now relatively quiet. If the outbreak currently occurring in some areas of the country reaches this region, it could be a perfect storm.
Is it possible to distinguish between the symptoms of dengue and Chikungunya?
Clinically, it is almost impossible [a doctor cannot know what the disease is based solely on the patient’s symptoms]. It’s so difficult to distinguish one from the other that the World Health Organization [WHO] recommends that suspected cases of dengue and Chikungunya both be treated as dengue.
Why?
Because dengue kills. And it kills quickly. Chikungunya, on the other hand, progresses slowly and is rarely fatal. Dengue mortality drops significantly if it is diagnosed early and treated, and Brazil generally does this very well. One consequence, however, is that everything ends up being reported as dengue.
What might be the impact of the simultaneous circulation of four dengue serotypes? Could more cases of severe dengue occur?
We are moving towards a situation of hyperendemicity, which is the simultaneous circulation of all four serotypes of the virus. We experienced this between 2007 and 2010, but not aggressively—each serotype was predominant in a different region, with two at most circulating at the same time. The exception was Manaus, where there was an epidemic of all four serotypes in 2010 and 2011.
Léo Ramos Chaves / Pesquisa FapespA Technician at FAMERP’s Virology Research Laboratory performs rapid dengue testsLéo Ramos Chaves / Pesquisa Fapesp
What are the consequences of a hyperendemic disease?
When a person is successively infected with different serotypes, the occurrence of severe dengue, which used to be known as hemorrhagic dengue, is more likely. In the first six months after infection with one serotype, the patient is protected against all serotypes due to nonspecific antibodies that remain in the blood. Between nine months and two years after infection, the level of antibodies drops, and they can actually facilitate infection by other serotypes. This phenomenon is called antibody-dependent enhancement, or ADE, which contributes to the occurrence of severe dengue. After two years has passed, a previous infection neither protects against nor worsens the following one. The consequences of the simultaneous circulation of all four serotypes depends on the circumstances. In São José do Rio Preto, we had a dengue type 2 epidemic in 2019. In 2022 and 2023, it was dengue type 1. If serotype 3 spreads in the area this year, there will be a major risk of more cases of hemorrhagic fever.
Dengue treatment is palliative, consisting of hydration and medication for pain and fever. Why is it so important to hydrate?
Because of vascular leakage. Due to increased permeability of the blood vessels, some of the liquid inside escapes from the patient’s circulatory system and accumulates in the surrounding tissue. This can lead to something known as hypovolemic shock. Since the blood volume is lower, the heart is unable to pump enough of it to the organs, which then fail.
Do the serotypes cause different severities of the disease?
Yes, the Asian-American lineage of serotype 2 that circulates in Brazil is more aggressive than the American lineage, which existed here in the past. And serotype 4 is typically less aggressive. This is a generalization, of course. If an individual is infected with dengue type 4 soon after a type 2 infection, ADE might occur and the case could become severe. A serotype 4 infection in a person who is obese or has diabetes can also be serious. From a public health perspective, it is important to know which strain is circulating. But in terms of patient care, dengue is dengue. Doctors must follow the same treatment protocols.
Butantan-DV protects against serotypes 1 and 2, but we do not know how it works against 3 and 4, which have not circulated in recent years. Is it still possible to measure the efficacy against these serotypes before the end of the trial?
I don’t think so. The number of people being followed is small. As a researcher, I don’t see a problem with serotypes 3 and 4. The Butantan vaccine was formulated with live attenuated viruses. The serotype 1, 3, and 4 viruses they used were subject to genetic deletions that impair their ability to reproduce. Since this process didn’t affect the reproduction capacity of serotype 2, another approach was used: serotype 2 genes were introduced into the serotype 4 virus, with low reproduction capacity. The data from animal and human trials show that all four components multiply in the body, stimulating the immune system. This does not occur with the other two vaccines approved for use in Brazil. With Sanofi’s vaccine, Dengvaxia, only the dengue serotype 4 component multiplies. With Takeda’s vaccine, Qdenga, it is only serotype 2 and maybe type 1. Sanofi’s vaccine does not protect against serotypes 1 and 2, while Takeda’s does not protect children against serotype 3 [probably because each vaccine uses a different technology]. With Butantan-DV, the weakest component is dengue 2, but there was still excellent protection against this serotype. There is no reason to expect protection against dengue types 3 and 4 to be any worse. But this is a hypothesis. Whether regulatory agencies will accept the results is a matter that Butantan will have to deal with.
How can they assess the efficacy against serotypes 3 and 4?
There are two ways. MerckSharp&Dohme, which is developing a vaccine almost identical to Butantan’s, is carrying out a phase 3 clinical study in Asia, where subtypes 3 and 4 are more common. This may take some time. Another option is human challenge studies, in which a person who has been given the vaccine is then deliberately exposed to the virus. Anna Durbin’s group at Johns Hopkins University, USA, is carrying out this type of experiment. If the regulatory agencies accept the data, they could fast-track licensing of the Butantan vaccine.
Is Butantan-DV expected to complement the role of the two existing vaccines or compete with them?
I don’t think they will compete. The data available so far suggest that the Butantan vaccine is superior to the others. Brazil is a country of 200 million inhabitants. It’s not possible to manufacture that many vaccines in one year. Takeda alone cannot supply the demand. Smart strategies are needed to immunize as many people as possible within an appropriate timeframe and with the resources available.
Five million doses of Qdenga are expected to be available this year, which would be enough to vaccinate 2.5 million people. What impact could this have on the epidemic?
It would have a personal impact, which is undeniable. The 2.5 million people who receive the vaccine would be protected. In terms of public health, however, this is just 1% of the Brazilian population—it would not have a major impact on the ongoing epidemic. And I’m concerned about the Takeda vaccine’s lack of protection against dengue 3. We could eventually see a similar situation to Sanofi.
What do you mean?
Sanofi’s Dengvaxia functioned like a first infection in children who had never had dengue. When they were subsequently infected with serotype 2, they developed severe dengue fever. That’s why it was only recommended for people who have already had the disease. In those cases, it is efficient and works as a reinforcement. Qdenga showed worrying signs in the presence of dengue 3, with a lack of effectiveness and an increase in cases. A panel of experts from the Brazilian Society of Tropical Medicine [SBMT], of which I was a member, advised against the use of Qdenga by Brazil’s public health system [SUS] at that time. When the SBMT made this recommendation, we did not know what the vaccination strategy would be. The Brazilian Ministry of Health chose to give the vaccine to adolescents, a group that rarely faces major health problems. It’s an intelligent approach. The problem occurs with children. A study published in 2022 suggests that the vaccine does not stop children from being infected by dengue serotype 3. The number of serotype 3 cases in the study was very small, however, as was the proportion of people who had not previously had dengue. This reduces the statistical reliability of the result in relation to this serotype. The team of experts from the WHO that evaluated the vaccine did not consider this a problem and recommended it for use in adolescents, just like the Brazilian Ministry of Health. Qdenga is a good vaccine with potential for use in the health system. Sanofi’s vaccine also has potential.
But it was not approved.
It was not. It has only been approved for individual use by people who have already had dengue fever. An additional complication is that it requires three doses. All of these vaccines have potential for use in the public health system. But they must be used in an intelligent way, ensuring people aren’t exposed to risk. We cannot accept risk.
The major change on the horizon is the licensing of the Butantan vaccine, which seems far superior to others
How many people would have to be vaccinated to see a protective effect in an epidemic?
We don’t have enough information to know. There is a fundamental individual impact. Vaccinated people are 80% less likely to get sick. That’s great! I’ve had dengue fever three times and it’s a horrible illness. I didn’t have the severe form and I wasn’t hospitalized, but I felt really miserable. If I could have gotten the vaccine at the time, I would have been very happy to do so. It prevents a disease that has a huge personal impact and an indirect economic cost that we don’t usually measure in Brazil. Worldwide, millions of people take up to five days of sick leave from work every year.
No dengue vaccines are available universally through Brazil’s public health system, but they are available in the private sector. Should people get it if they can afford to?
That’s an individual decision that has to be made in consultation with a doctor.
A review article published in the journal BioDrugs in 2022 listed seven dengue vaccine candidates. The three most promising were those developed by Sanofi, Takeda, and Butantan. Are there others in development?
There are several others in earlier stages of testing. The major change on the horizon is the licensing of the Butantan vaccine, which seems far superior to the others.
Without vaccines for everyone, the solution is to control the vector. Brazil did this until the middle of the last century. Is it possible to do it again?
Nowadays it is impossible to eradicate the vector the way we did in the past. Two approaches used in the early twentieth century would not be accepted today. The first was the “foot in the door” policy adopted in campaigns to eradicate the Aedes aegypti mosquito. Health agents would enter your house with you, without you, or despite you. The public health merit of such an approach is worthy of discussion, but even so, it is no longer socially acceptable. The second was the use of pyrethroid insecticides and other highly toxic products, which would also no longer be accepted. We have been talking about vector control ever since dengue epidemics returned in Brazil in 1986. We have tried several strategies, but none succeeded. But there is something that seems to show potential: controlling vectorial capacity.
What is vectorial capacity?
It is the mosquito’s ability to transmit the disease. It means rather than trying to eradicate the mosquito itself, we instead reduce its capacity to transmit the virus. This has been attempted by releasing mosquitoes intentionally infected with bacteria of the genus Wolbachia, which colonizes the mosquito’s digestive tract and prevents the dengue, Zika, Chikungunya, and yellow fever viruses from infecting the intestinal cells and replicating. With the viruses unable to multiply, the levels in the salivary glands, from where they are injected during a bite, remain low. Transmission is thus interrupted. One of the big advantages is that when the mosquitoes reproduce in nature, they transmit the bacteria to their offspring. There has been major investment in this approach by the World Mosquito Program. The Brazilian Ministry of Health and FIOCRUZ [Fundação Oswaldo Cruz] have also invested heavily. Some of the data from preliminary studies show that the method is effective, but we are still waiting for the results of a large, controlled study underway in Belo Horizonte, Contagem, and Betim.
Tell us about the study.
We divided the municipalities of Belo Horizonte, Contagem, and Betim into 36 clusters. In some of them, we are releasing mosquitoes infected with Wolbachia alongside the usual vector control protocols. In others, we are only implementing normal vector controls. We are entering the fourth year of monitoring, but the results will only be released at the end of the experiment.
Does this represent another potential strategy?
Yes. There is no silver bullet. If someone had asked me eight years ago whether we could control dengue, I would have given them a pessimistic answer. Today, I am extremely optimistic.
What has changed?
We now have a three-pronged approach to combating dengue. There are two licensed vaccines that despite their limitations, are excellent tools if used well. And we have a third one on the way that is probably better. The second strategy is the use of mosquitoes infected with Wolbachia, which plays the role of significantly reducing transmission. And the third is that there are at least three antiviral drugs specific to dengue undergoing phase 2 and 3 clinical trials.
What else can be done?
Dengue is a disease that can be caught at home. It is up to each of us to take care of that aspect. We shouldn’t wait for the State to take care of our own backyards. We can’t solve everything, but we can reduce the problem. Since it isn’t possible to halt a dengue epidemic, what we have to do now that cases are rising is to prepare the health system for the high number of patients and raise awareness among the population about how to eliminate mosquito breeding grounds.
