Dengue Vaccines: Three Licensed Vaccines and What the Trials Found

Table of Contents

1. Why a Dengue Vaccine Is Hard to Make
2. The Three Licensed Vaccines at a Glance
3. CYD-TDV: The First Large Trials
4. CYD-TDV: The Safety Signal in People Never Infected Before
5. CYD-TDV: Limited to People With an Earlier Infection
6. TAK-003: The Trial Year by Year
7. TAK-003: Results by Virus Type
8. Butantan-DV: One Dose, Five Years of Follow-Up
9. Who Each Vaccine Is Recommended For
10. Side Effects as Reported
11. What the Trials Have Not Answered
12. Key Research Papers
13. Connections
14. Featured Videos

Why a Dengue Vaccine Is Hard to Make

Dengue is not one virus but four closely related ones, called serotypes and numbered dengue virus 1 to 4 (DENV-1 to DENV-4). A person can be infected four separate times in a lifetime, once by each type. Recovering from one type gives long protection against that type, but not against the other three.

The second difficulty is a problem called antibody-dependent enhancement. After a first dengue infection, the body carries antibodies that recognise the other types only partly. When a second, different type arrives, these antibodies can latch onto the virus without disabling it, and help it get into immune cells. That is why a second dengue infection carries a higher risk of severe dengue than the first.

A long-running study of children in Nicaragua, published in 2017, showed this in people, not just in laboratory dishes or animals. The risk of severe dengue was highest in children whose earlier antibody levels fell within a narrow middle range. Children with high antibody levels were protected from all symptomatic dengue. The researchers wrote that for vaccine development, "enhancement, not just lack of protection, is of concern."

This shapes everything below. A vaccine that protects well against some types but poorly against others could, in theory, act like a first infection and leave a person primed for a worse illness later. Vaccine makers therefore have to show protection against all four types, and trials have to follow people for years, keeping separate counts for people who had dengue before vaccination and people who had not.

The Three Licensed Vaccines at a Glance

All figures below come from the published trials and reviews listed in Key Research Papers.

CYD-TDV is a chimeric vaccine built on the backbone of the yellow fever 17D vaccine virus, according to the United States Advisory Committee on Immunization Practices. TAK-003 is built on a weakened dengue virus 2 backbone, according to a 2025 review by its developers. The Butantan-DV trial report states that its vaccine technology was licensed to the Butantan Institute, a non-profit public health institution of the state of São Paulo, from the US National Institutes of Health.

A 2026 review of travel vaccines states that TAK-003 is authorized in more than 40 countries, that Butantan-DV is licensed in Brazil, and that manufacturing of CYD-TDV has been discontinued.

CYD-TDV: The First Large Trials

CYD-TDV was the first dengue vaccine to complete a phase 3 trial, the large final stage of testing. Two trials ran side by side.

The Asian trial, published in 2014, enrolled 10,275 children aged 2 to 14 in five countries in the Asia-Pacific region. Two in every three received the vaccine and one in three received a placebo, as three injections at months 0, 6 and 12. From 28 days after the third injection to the end of follow-up at month 25, the vaccine prevented 56.5% of symptomatic dengue cases confirmed by laboratory test.

The Latin American trial, published in 2015, enrolled 20,869 children aged 9 to 16 in five countries. In a subgroup tested before vaccination, 79.4% had already had at least one dengue infection. Protection against confirmed dengue was 60.8% in the main analysis and 64.7% when every child who received at least one injection was counted. Protection was uneven across the four virus types: 50.3% for type 1, 42.3% for type 2, 74.0% for type 3 and 77.7% for type 4. Protection against hospital admission for dengue was 80.3%, and only 1 of 12 severe cases occurred in the vaccine group.

When the two trials were pooled over the first 25 months, protection was 60.3% overall, 65.6% in children aged 9 or older and 44.6% in children younger than 9.

CYD-TDV: The Safety Signal in People Never Infected Before

The trials kept following the children after the first two years, counting hospital admissions for dengue as a safety measure. In the third year, a problem appeared in the youngest children. Across the three trials combined, the relative risk of being admitted to hospital with dengue was 1.58 among children under 9 (meaning about 58% more admissions in the vaccine group, although the range of uncertainty included no difference), and 0.50 among children aged 9 or older (half as many). Hospital admission for severe dengue in year 3 occurred in 18 of 22,177 vaccinated children and 6 of 11,089 children given placebo. The authors described the higher hospital rate in children under 9 as "unexplained."

A four-year follow-up, published in 2018, found that over years 1 to 4 vaccinated children overall were about half as likely to be admitted to hospital with dengue (relative risk 0.511), and children aged 9 or older about a third as likely (0.324). In children aged 2 to 5, there were more hospital cases in the vaccine group in year 3 but not in year 4.

The explanation came from a reanalysis published in 2018. Researchers developed a new blood test to work out which children had been infected with dengue before vaccination. Among children aged 2 to 16 who had never been infected, 3.06% of vaccinated children were admitted to hospital with dengue over five years, compared with 1.87% of children given placebo (hazard ratio 1.75). Among children aged 9 to 16 who had never been infected, the figures were 1.57% and 1.09% (hazard ratio 1.41, a range of uncertainty that included no difference). Severe dengue showed the same trend.

In children who had been infected before, the picture reversed. Hospital admissions were about 68% lower in vaccinated children aged 2 to 16 (hazard ratio 0.32) and about 79% lower in those aged 9 to 16 (0.21). The authors concluded that CYD-TDV protected against severe dengue and hospital admission for five years in people who had been exposed to dengue before vaccination, and that there was evidence of a higher risk in vaccinated people who had not.

The United States advisory committee describes the mechanism in plain terms: CYD-TDV is associated with an increased risk of severe dengue in people who experience their first natural dengue infection after vaccination.

CYD-TDV: Limited to People With an Earlier Infection

The World Health Organization's vaccine advisory group, the Strategic Advisory Group of Experts on Immunization (SAGE), first issued recommendations on CYD-TDV in April 2016. After the serostatus reanalysis was announced in November 2017, the group weighed two options: vaccinating whole populations where more than 80% of people had already had dengue, or testing each person first and vaccinating only those with an earlier infection. In April 2018 it chose the second option, the pre-vaccination screening strategy.

In the United States, the Food and Drug Administration (FDA) licensed CYD-TDV for children and adolescents aged 9 to 16. In 2021 the Advisory Committee on Immunization Practices recommended it for children aged 9 to 16 who live where dengue is endemic and who have evidence of an earlier dengue infection, such as a positive result on a highly specific antibody blood test. The committee lists the endemic US areas as Puerto Rico, American Samoa, the US Virgin Islands, the Federated States of Micronesia, the Republic of Marshall Islands and the Republic of Palau.

The committee set a standard for these screening tests: at least 98% specificity (few false positives, so that people never infected are not wrongly vaccinated) and at least 75% sensitivity. A 2024 study of tests on blood from children in Puerto Rico found that some available antibody tests met or came close to these figures, with the best reaching 84.5% sensitivity and 97.1% specificity, or 76.2% sensitivity and 98.1% specificity.

The need to test every person before vaccination, plus three injections over a year, limited how widely CYD-TDV was used. A 2026 review reports that its manufacture has now been discontinued.

TAK-003: The Trial Year by Year

TAK-003 was tested in a single large trial of 20,099 children and teenagers aged 4 to 16 at 26 centres in Brazil, Colombia, the Dominican Republic, Nicaragua, Panama, the Philippines, Sri Lanka and Thailand. Two in three received the vaccine and one in three a placebo, as two injections three months apart. Unlike the CYD-TDV trials, every child's blood was tested before vaccination, so results could be reported separately for children who had and had not had dengue before. Any child with a fever was tested for dengue by a laboratory method that also identifies the virus type.

The results changed over time, and the trial published each stage:

• First year (2019): 80.2% protection against confirmed dengue in the main analysis, and 95.4% against dengue leading to hospital admission (5 admissions in the vaccine group compared with 53 in the placebo group). In children with no earlier infection, about 27.7% of the group, protection was 74.9%.
• 18 months (2020): 73.3% overall, 76.1% in children with an earlier infection, 66.2% in children without one, 90.4% against hospital admission and 85.9% against dengue hemorrhagic fever.
• About 2 years (2022): 72.7% overall, with protection in the second year alone falling to 56.2%. The largest drop was in children aged 4 to 5, where second-year protection was 24.5% with a range of uncertainty that included no effect. It was 60.6% in children aged 6 to 11 and 71.2% in those aged 12 to 16.
• About 4.5 years (2024): 91.0% of children completed follow-up. In total, 1,007 confirmed dengue cases occurred (560 in the placebo group and 447 in the vaccine group, out of a placebo group half the size), and 188 needed hospital care (142 placebo, 46 vaccine). Protection was 61.2% against confirmed dengue and 84.1% against hospital admission. In children with no earlier infection, it was 53.5% and 79.3%.

So protection against any dengue fell over the years, while protection against being admitted to hospital stayed higher. The authors of the two-year report wrote that changes in which virus type was circulating each year partly explained the year-to-year differences, because the vaccine's effect varies by type.

TAK-003: Results by Virus Type

At 18 months, protection by virus type was 69.8% against type 1, 95.1% against type 2, 48.9% against type 3 and 51.0% against type 4. For type 4 the range of uncertainty ran from −69.4% to 85.8%, meaning the trial could not show an effect either way.

The 4.5-year report looked at virus type and earlier infection together, as an exploratory analysis:

This gap is the main open question for TAK-003. A 2025 review by World Health Organization authors states that concerns remain about vaccine-enhanced disease, particularly among people with no earlier infection who are later exposed to type 3 and type 4. The trial authors' own conclusion was that TAK-003 showed long-term protection against all four types in people previously exposed, and against types 1 and 2 in people never infected.

Butantan-DV: One Dose, Five Years of Follow-Up

Butantan-DV is given as one injection of 0.5 mL under the skin, containing roughly 1,000 infectious units of each of the four vaccine virus strains. Its phase 3 trial in Brazil enrolled 16,235 people aged 2 to 59 between February 2016 and July 2019: 10,259 received the vaccine and 5,976 a placebo. Participants were grouped by age into 2–6, 7–17 and 18–59 years.

The trial published three stages:

• 2 years (2024): 79.6% protection overall, 73.6% in people with no earlier dengue and 89.2% in people with an earlier infection. By age, it was 80.1% at 2–6 years, 77.8% at 7–17 and 90.0% at 18–59. Protection was 89.5% against type 1 and 69.6% against type 2.
• Mean 3.7 years (2024): 356 confirmed dengue cases (128 in the vaccine group, 228 in the placebo group), for 67.3% protection.
• 5 years (2026): 65.0% protection overall, 77.1% in people with an earlier infection, 58.9% in people without one, 73.0% against type 1 and 55.7% against type 2. Protection against dengue with warning signs or severe dengue, counted together, was 80.5%.

Through the whole trial, no dengue cases caused by type 3 or type 4 occurred, because those types were not circulating in the study areas. The trial therefore has no measure of how well Butantan-DV protects against them.

Brazil's drug regulator, Anvisa, approved Butantan-DV in November 2025 for people aged 12 to 59. In June 2026, Brazil's National Immunization Program and Anvisa temporarily suspended vaccination with it. Between January and May 2026, among more than 500,000 people vaccinated, 42 people had developed an illness resembling dengue with warning signs, and there were three severe cases, two of them deaths (about 0.008% of those vaccinated). The Ministry of Health said there was not yet enough evidence to conclude that the vaccine caused these illnesses, and described the suspension as a precaution during the investigation. The Brazilian Society of Immunizations reported these figures in its statement of 11 June 2026 (SBIm position statement). The sources read for this page do not report the outcome of the investigation.

Who Each Vaccine Is Recommended For

These are the positions of the named bodies, reported as published.

• CYD-TDV, World Health Organization (2018): SAGE adopted a pre-vaccination screening strategy, so that only people with confirmed earlier dengue infection are vaccinated. An earlier expert-group summary of the WHO position lists people aged 9 or older.
• CYD-TDV, United States (2021): licensed by the FDA for ages 9 to 16; the Advisory Committee on Immunization Practices recommends it for children aged 9 to 16 with laboratory evidence of earlier dengue infection who live in areas where dengue is endemic. Its manufacture has since been discontinued.
• TAK-003, World Health Organization: SAGE recommends that TAK-003 be considered for public programmes in high-transmission areas for people aged 6 to 16, according to a 2025 review. A 2025 review by WHO authors adds that WHO recommends targeted introduction in high-transmission settings without pre-vaccination screening.
• Butantan-DV: licensed in Brazil, according to a 2026 review.

Decisions about vaccines for an individual, including for travel, belong with a clinician and the national immunization programme of the country concerned.

Side Effects as Reported

Because all three vaccines are live weakened viruses, they can multiply in the body for a short time after injection and cause symptoms that resemble a mild infection.

TAK-003. In pooled early-stage trials of 805 vaccinated people, vaccine virus genetic material was found in the blood of 54.8% (67.0% of those never infected before and 33.0% of those previously infected). It peaked in the second week after vaccination, appeared mostly after the first dose, and was most often the type 2 component. The most frequent reported side effects were pain at the injection site (42.0% in people without vaccine virus in the blood, 46.8% in people with it) and headache (36.6% and 37.6%). Pain, redness, rash, joint pain and tiredness were more common in people with vaccine virus in the blood; the authors described these symptoms as passing and mild to moderate. In the main trial, serious adverse events were similar in the vaccine and placebo groups: 3.1% and 3.8% in the first report, 4.0% and 4.8% at 18 months, and 5.0% and 5.9% in the later follow-up period. Seventeen deaths occurred (11 in the vaccine group and 6 in the placebo group, out of a placebo group half the size), and none were considered related to the vaccine.

Butantan-DV. Within 21 days of the injection, side effects across the whole body that investigators judged related to the injection were reported by 58.3% of vaccinated participants and 45.6% of those given placebo. The most common was headache, reported by 36.7% of vaccine recipients and 31.1% of placebo recipients, mostly at the mildest grade. Serious adverse events over the trial were similar: 6.2% in the vaccine group and 6.6% in the placebo group. Over 5 years, the investigators reported no safety concerns.

CYD-TDV. In the Asian trial, serious adverse events within 28 days of an injection occurred in 1% of both groups, and were mainly infections and injuries consistent with ordinary childhood illness. The Latin American trial reported a safety profile similar to placebo. The main safety finding for CYD-TDV is the delayed one described above: the higher risk of hospital-level and severe dengue in vaccinated people never infected before.

What the Trials Have Not Answered

• Type 3 and type 4. TAK-003 showed no protection against type 3 in people never infected before, and had too few type 4 cases to judge. Butantan-DV saw no type 3 or type 4 cases at all.
• Waning protection. TAK-003 protection against any dengue fell from about 80% in the first year to 61.2% over 4.5 years. The 2025 developer review states that the effect of a booster dose is being studied.
• Adults and people at higher risk. The TAK-003 efficacy trial enrolled only ages 4 to 16. A 2026 review states that more real-world data are needed, particularly for vaccinated people never infected before and for older, immunocompromised or medically at-risk adults. All three licensed vaccines are live; the review names single-dose vaccines that are not live, suitable for high-risk groups, as a research priority.
• Real-world performance. Trial results come from children and adults followed closely in study centres. The 2026 review describes long-term and post-marketing data that continue to refine understanding of protection by virus type, waning immunity and rare adverse events.

Key Research Papers

1. Katzelnick LC, Gresh L, Halloran ME, Mercado JC, Kuan G, Gordon A, et al. Antibody-dependent enhancement of severe dengue disease in humans. Science. 2017;358(6365):929-932. PubMed PMID: 29097492
2. Capeding MR, Tran NH, Hadinegoro SR, Ismail HI, Chotpitayasunondh T, Chua MN, et al. Clinical efficacy and safety of a novel tetravalent dengue vaccine in healthy children in Asia: a phase 3, randomised, observer-masked, placebo-controlled trial. Lancet. 2014;384(9951):1358-65. PubMed PMID: 25018116
3. Villar L, Dayan GH, Arredondo-García JL, Rivera DM, Cunha R, Deseda C, et al. Efficacy of a tetravalent dengue vaccine in children in Latin America. N Engl J Med. 2015;372(2):113-23. PubMed PMID: 25365753
4. Hadinegoro SR, Arredondo-García JL, Capeding MR, Deseda C, Chotpitayasunondh T, Dietze R, et al. Efficacy and Long-Term Safety of a Dengue Vaccine in Regions of Endemic Disease. N Engl J Med. 2015;373(13):1195-206. PubMed PMID: 26214039
5. Arredondo-García JL, Hadinegoro SR, Reynales H, Chua MN, Rivera Medina DM, Chotpitayasunondh T, et al. Four-year safety follow-up of the tetravalent dengue vaccine efficacy randomized controlled trials in Asia and Latin America. Clin Microbiol Infect. 2018;24(7):755-763. PubMed PMID: 29408333
6. Sridhar S, Luedtke A, Langevin E, Zhu M, Bonaparte M, Machabert T, et al. Effect of Dengue Serostatus on Dengue Vaccine Safety and Efficacy. N Engl J Med. 2018;379(4):327-340. PubMed PMID: 29897841
7. Wilder-Smith A, Hombach J, Ferguson N, Selgelid M, O'Brien K, Vannice K, et al. Deliberations of the Strategic Advisory Group of Experts on Immunization on the use of CYD-TDV dengue vaccine. Lancet Infect Dis. 2019;19(1):e31-e38. PubMed PMID: 30195995
8. Paz-Bailey G, Adams L, Wong JM, Poehling KA, Chen WH, McNally V, et al. Dengue Vaccine: Recommendations of the Advisory Committee on Immunization Practices, United States, 2021. MMWR Recomm Rep. 2021;70(6):1-16. PubMed PMID: 34978547
9. Medina FA, Vila F, Adams LE, Cardona J, Carrion J, Lamirande E, et al. Comparison of the sensitivity and specificity of commercial anti-dengue virus IgG tests to identify persons eligible for dengue vaccination. J Clin Microbiol. 2024;62(10):e0059324. PubMed PMID: 39194193
10. Biswal S, Reynales H, Saez-Llorens X, Lopez P, Borja-Tabora C, Kosalaraksa P, et al. Efficacy of a Tetravalent Dengue Vaccine in Healthy Children and Adolescents. N Engl J Med. 2019;381(21):2009-2019. PubMed PMID: 31693803
11. Biswal S, Borja-Tabora C, Martinez Vargas L, Velásquez H, Theresa Alera M, Sierra V, et al. Efficacy of a tetravalent dengue vaccine in healthy children aged 4-16 years: a randomised, placebo-controlled, phase 3 trial. Lancet. 2020;395(10234):1423-1433. PubMed PMID: 32197105
12. López-Medina E, Biswal S, Saez-Llorens X, Borja-Tabora C, Bravo L, Sirivichayakul C, et al. Efficacy of a Dengue Vaccine Candidate (TAK-003) in Healthy Children and Adolescents 2 Years after Vaccination. J Infect Dis. 2022;225(9):1521-1532. PubMed PMID: 33319249
13. Tricou V, Yu D, Reynales H, Biswal S, Saez-Llorens X, Sirivichayakul C, et al. Long-term efficacy and safety of a tetravalent dengue vaccine (TAK-003): 4·5-year results from a phase 3, randomised, double-blind, placebo-controlled trial. Lancet Glob Health. 2024;12(2):e257-e270. PubMed PMID: 38245116
14. Tricou V, Saez-Llorens X, Kosalaraksa P, Reynales H, Sirivichayakul C, Borja-Tabora C, et al. Characterization of vaccine viremia, attenuation reversion, and safety: Combined results from the TAK-003 dengue vaccine clinical development program. Vaccine. 2026;88:128917. PubMed PMID: 42497670
15. Sáez-Llorens X, DeAntonio R, Low JGH, Kosalaraksa P, Dean H, Sharma M, et al. TAK-003: development of a tetravalent dengue vaccine. Expert Rev Vaccines. 2025;24(1):324-338. PubMed PMID: 40207772
16. Kallás EG, Cintra MAT, Moreira JA, Patiño EG, Braga PE, Tenório JCV, et al. Live, Attenuated, Tetravalent Butantan-Dengue Vaccine in Children and Adults. N Engl J Med. 2024;390(5):397-408. PubMed PMID: 38294972
17. Nogueira ML, Cintra MAT, Moreira JA, Patiño EG, Braga PE, Tenório JCV, et al. Efficacy and safety of Butantan-DV in participants aged 2-59 years through an extended follow-up: results from a double-blind, randomised, placebo-controlled, phase 3, multicentre trial in Brazil. Lancet Infect Dis. 2024;24(11):1234-1244. PubMed PMID: 39116904
18. Kallás EG, Moreira JA, Patiño EG, Braga PE, Tenório JCV, Alves LBO, et al. Long-term efficacy and safety of the single-dose tetravalent Butantan dengue vaccine. Nat Med. 2026;32(4):1393-1400. PubMed PMID: 41781546
19. Wilder-Smith A, Cherian T, Hombach J. Dengue Vaccine Development and Deployment into Routine Immunization. Vaccines (Basel). 2025;13(5):483. PubMed PMID: 40432095
20. Torres JR, Falleiros-Arlant LH, Gessner BD, Delrieu I, Avila-Aguero ML, Giambernardino HIG, et al. Updated recommendations of the International Dengue Initiative expert group for CYD-TDV vaccine implementation in Latin America. Vaccine. 2019;37(43):6291-6298. PubMed PMID: 31515144
21. Norman FF, McGuinness SL, Chen LH. Dengue and chikungunya vaccines past, present and future: implications for travelers. Curr Opin Infect Dis. 2026;39(5):404-414. PubMed PMID: 42296464
22. Sociedade Brasileira de Imunizações (SBIm). Suspensão temporária da vacinação contra a dengue com a Butantan-DV. Position statement, 11 June 2026. SBIm statement (PDF)

PubMed Topic Searches

1. PubMed: CYD-TDV and dengue serostatus
2. PubMed: TAK-003 efficacy
3. PubMed: Butantan-DV
4. PubMed: antibody-dependent enhancement and dengue vaccines
5. PubMed: dengue pre-vaccination screening tests

Connections

• Dengue Fever — the main page: the illness, warning signs and care
• Yellow Fever — the related virus whose 17D vaccine strain is the CYD-TDV backbone
• Max Theiler — developer of the yellow fever 17D vaccine
• Zika Virus — another virus spread by the same mosquitoes
• Chikungunya — a mosquito-borne infection that now has its own vaccines
• Viral Hemorrhagic Fevers — the wider group that includes severe dengue
• How Vaccines Train Your Immune System — an animation of how vaccines work
• Malaria Prevention: Nets, Prophylaxis, and Vaccines — vaccines against another mosquito-borne disease

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