TV005 dengue vaccine protects against dengue serotypes 2 and 3 in two controlled human infection studies

BACKGROUND Disease due to dengue viruses is a growing global health threat, causing 100–400 million cases annually. An ideal dengue vaccine should demonstrate durable protection against all 4 serotypes in phase III efficacy trials, however the lack of circulating serotypes may lead to incomplete efficacy data. Controlled human infection models help downselect vaccine candidates and supply critical data to supplement efficacy trials. We evaluated the efficacy of a leading live-attenuated tetravalent dengue vaccine candidate, TV005, against infection with a newly established dengue serotype 3 or an established serotype 2 challenge virus. METHODS Two randomized, controlled clinical trials were performed. In study 1, a total of 42 participants received TV005 or placebo (n = 21 each), and 6 months later, all were challenged with dengue 2 virus (rDEN2Δ30) at a dose of 103 PFU. In study 2, a total of 23 participants received TV005 and 20 received placebo, and 6 months later, all were challenged with 104 PFU dengue 3 virus (rDEN3Δ30). The study participants were closely monitored for safety, viremia, and immunologic responses. Infection, measured by post-challenge viremia, and the occurrence of rash and neutropenia were the primary endpoints. Secondary endpoints included safety, immunologic, and virologic profiles following vaccination with TV005 and subsequent challenge with the rDEN2Δ30 or rDEN3Δ30 strain. RESULTS TV005 was well tolerated and protected all vaccinated volunteers from viremia with DENV2 or DENV3 (none infected in either group). Placebo recipients had post-challenge viremia (100% in study 1, 85% in study 2), and all experienced rash following challenge with either serotype. CONCLUSIONS TV005 is a leading tetravalent dengue vaccine candidate that fully protected against infection with DENV2 and DENV3 in an established controlled human infection model. TRIAL REGISTRATION ClinicalTrials.gov NCT02317900 and NCT02873260. FUNDING Intramural Research Program, NIH (contract HHSN272200900010C).


Introduction
Dengue viruses are estimated to cause 100-400 million symptomatic illnesses each year with a significant and expanding burden of severe disease and mortality in both endemic populations and travelers (1)(2)(3)(4).The geographic distribution of dengue is also expanding (5).All four serotypes of dengue viruses (DENV1-4) cause symptomatic disease and can circulate independently or concurrently.Severe disease manifestations include hemorrhagic fever, plasma leakage leading to shock, and death.Management is solely supportive; to date, specific therapeutics are not available for use (6).
The development of a vaccine that is safe and effective against all four serotypes has been a global priority (7).Importantly, individuals experiencing a second dengue infection with a new serotype appear to be at higher risk for more severe disease.Partial serotype-specific immunity conferred by the first infection may facilitate increased viral entry and enhance replication of a subsequent serotype.Thus, a successful tetravalent dengue vaccine should concurrently protect against all four serotypes.Dengue vaccines in advanced development are all live-attenuated tetravalent vaccines (LATV), since the immunogenicity of LATV is superior to other vaccine designs (e.g.inactivated, subunit, DNA) (8).LATV induce both robust humoral and cellular immunity, present viral epitopes in their native conformation, and are generally less expensive to produce (8).Three LATV are in late-stage development, those of the National Institute of Health (NIH), TV003 and TV005 vaccines (9) and Takeda TAK-003 (10).Sanofi Pasteur's tetravalent vaccine, Dengvaxia®, was first licensed in 2015 in Mexico.Due to observations of increased disease-related hospitalizations in DENV-naïve vaccine recipients, it is now recommended by the US Food and Drug Administration (FDA), the European Medicines Agency, and World Health Organization for use only in previously dengue-exposed individuals (11).Similar concerns have been raised with the Takeda TAK-003 vaccine (7,12,13).
Relevant to this work, the NIH dengue vaccines are attenuated by the deletion of nucleotides from 3' untranslated region (UTR) of the viral genome (8).These vaccines contain structural and non-structural proteins derived solely from DENV, with full-length genomes of DENV1,3,4 serotypes and a chimeric genome for DENV2 serotype.Dengue strains used in the TV005 vaccine are rDENV1∆30, rDEN2/4∆30 (New Guinea C [NGC] strain), rDEN3∆30/31, and rDENV4∆30.10 3 plaque-forming units (PFU) of each serotype is included in TV003.TV005 is identical except an increased dosage (10 4 PFU) of the DENV2 component, designed after early phase I trials suggested lower immunogenicity to DENV2 (14).Although subsequent clinical trials have eliminated this early concern (15), both TV003 and TV005 have progressed in development toward licensure internationally for further development by multiple pharmaceutical companies (9).The immunogenicity of both vaccines benefits from a transient low-level viremia, as expected for a live vaccine (14).Both formulations elicit cellular immune responses to the non-structural components and tetravalent neutralizing homotypic antibodies responses in the majority of subjects (16)(17)(18).
Advanced development of LATV prompted conversations about what safety and efficacy data should precede and/or supplement large scale testing of a tetravalent vaccine in dengue-endemic settings (13).To this end, our team employs controlled human infection models (CHIMs), which studied alongside vaccines, are important tools that provide early measures of vaccine efficacy to specific serotypes, and complement phase III trials.Notably, if efficacy is not demonstrated using a CHIM, a LATV may be modified or eliminated before reaching large efficacy trials (19).The challenge virus strains themselves (DENV2 [Tonga/74], and DENV3 [Sleman/78]) are derived from dengue outbreaks in Tonga and Indonesia, respectively, associated with relatively mild clinical disease, low viremia levels, and few hemorrhagic manifestations and thus can be considered as naturally attenuated DENV strains (20,21).The clinical products used in the challenge model are recombinant versions designed from very low passage isolates that were also engineered to contain the ∆30 mutation with an original goal of using them as vaccine candidates.Studies in nonhuman primates indicated that the DEN2∆30 (Tonga/74) and DEN3∆30 (Sleman/78) were not significantly attenuated compared to their wildtype parent viruses (22,23).Although the ∆30 mutation was attenuating for other serotypes/strains of DENV such a DENV-1 and DENV-4, the ∆30 mutation did not confer an additional attenuation phenotype to DENV2 Tonga/74 or DENV3 Sleman/78 and the ∆30 derivatives were demonstrated in Phase I testing to be too reactogenic as vaccine candidates (9).
With the ultimate goal of developing an affordable vaccine for the most at-risk populations, particularly dengue-naïve children and adults, NIH tetravalent vaccines have been developed over two decades of methodical and iterative studies, beginning with testing of each monovalent vaccine, followed by evaluation of tetravalent vaccine admixtures and now, human experimental infections (CHIM) and Phase III trials.This process has determined homotypic immunogenicity to all serotypes, inoculum size, use of a single dose, and vaccine safety in individuals up to 70 years of age and has included subjects in the United States, Thailand, Brazil, and Bangladesh.In addition, our initial evaluation of TV003 in a CHIM demonstrated complete protection against infection with a DEN2 challenge virus six months after vaccination (15).
Herein, using two randomized, controlled clinical trials, our objectives were to confirm the efficacy of the second NIH tetravalent vaccine (TV005) against DENV2 (DENV2Δ 30, Tonga strain) or DENV 3 (DENV3Δ 30/Sleman 78) infection.This work was the first use of our DENV3 attenuated challenge virus to test efficacy of any LATV.Our secondary objectives included safety, immunologic, and virologic profiles of subjects receiving TV005 and the subsequent DENV2 or DENV3 challenge strains.

Results:
Following screening, 319 subjects were evaluated for participation and 98 were randomized to receive TV005 vaccine or placebo (48 in study 1, and 50 in study 2) and were monitored as described.Viral challenge of all subjects occurred six months after vaccination, in both studies.42 subjects in study 1 (21 each TV005 and placebo) were given the DENV2∆30 challenge virus.In study 2, 43 subjects (23 received TV005 and 20 received placebo) were given the DENV3∆30 challenge virus.As noted on Figure 1, 13 subjects were removed from the study before viral challenge for medical ineligibility, incarceration, conflict of interest, or withdrawal of consent; 2 subjects in study 2 were replaced as they withdrew prior to study day 28 (kept for safety evaluation).
Demographic data for subjects in both studies is shown on Table 1; significant differences were not noted between the groups when age, gender and race were evaluated.
Measures of Efficacy: As shown on Table 2, the TV005 vaccine protected all vaccinated individuals from both viremia (primary efficacy endpoint) and rash following challenge six months after vaccination with either DENV2 or DENV3.In contrast, in subjects who did not receive the TV005 vaccination and who subsequently received the DENV2 challenge virus, all subjects had DENV2 viremia (n=21, 100%).For placebo recipients who subsequently received the DENV3 challenge strain, 17 (85%) had DENV3 viremia.
Viremia titers post-vaccination and challenge are shown in Table 3.Following challenge, DENV2 viremia by direct culture had a mean peak titer of 2.23 log PFU/mL and maximum peak titer of 3.2 log10 PFU/mL, with a mean duration of 4.6 (range 2-6) days.DENV3 challenge viremia was lower (mean peak titer 1.07 log10 PFU/mL, maximum 2.2 log10 PFU/mL) and shorter mean duration of 2 (range 1-5) days.
Following DENV2 or DENV3 viral challenge, all (100%) placebo recipients in both studies had rash.Neutropenia (defined as absolute neutrophil count [ANC] of <1000 cells/mm 3 ) was not a statistically significant marker of vaccine efficacy.
Safety and Reactogenicity to TV005 Vaccination: Adverse events were minimal and are shown in Table 4.As anticipated based on past studies, significant associations with vaccination were mild rash in 30 (62.5%), injection site erythema in 6 (12.5%), and a mild, short-lived neutropenia in 6 (12.5%) vaccinees.
Safety and Reactogenicity to viral challenges: Following receipt of the DENV2 challenge strain (Table 5 and Fig 2 ), adverse events were noted predominately in the placebo recipients, including myalgias and retro-orbital pain, and cytopenia.ANC <1000 cells/mm 3 did not differ between groups but significant differences were noted with % decline in ANC, as well as for lymphocytes and platelets.Similarly, as seen in Table 6 and Fig  The adverse events following DENV2 and DENV3 challenge were compared, including subject data from two previous DENV2∆30 CHIM studies (15,19) and one previous DENV3∆30 CHIM study (24).All viral challenges were six months after vaccination.As shown in Table 7, and despite the lower viremia (as above), the DENV3 CHIM is associated with significantly more local adverse events (erythema, induration, tenderness) at the injection site, as well as systemic symptoms of fatigue and headache, compared to DENV2 CHIM.Fever was not seen in either CHIM, except in a single DENV3 challenge volunteer, and significant differences were not found in the occurrence of cytopenias, or in liver function tests.Severity and duration of rash in the two models is detailed in Table 8. 9): Following TV005 vaccination, with data from both studies combined, neutralizing antibody responses consistent with seroconversion and seropositivity to all serotypes were found in the majority of vaccine recipients: from 79% (DENV1) to 100% (DENV2).100% of vaccinees had serologic responses to three serotypes (trivalent response) and 72% had a tetravalent response (Figure 3)
For subjects who received the TV005 vaccine, seropositivity and GMT did not change markedly following viral challenge with DENV2 or 3 and boosting (of seropositivity or GMT) was not observed (Table 10, Figure 4).

Discussion:
Leveraging controlled human infection models (CHIM) that use DENV2 and DENV3 challenge viral strains, we demonstrate that the NIH live-attenuated tetravalent dengue vaccine TV005 provides complete (100%) protective efficacy against infection with DENV2 or DENV3 six months after vaccination of dengue-naïve individuals.Use of CHIM allows assessment of vaccine efficacy from known serotypes, using controlled inoculum, a known time of infection, and close clinical observation.This work represents the first CHIM-based demonstration of efficacy of the tetravalent TV005 vaccine to prevent infection with DENV2 and DENV3.This is the first report of vaccine efficacy testing using the DENV∆30 CHIM and the largest study thus far with a DENV3 challenge strain.
Both rDENV2∆30 and rDENV3∆30 challenge models were tested for safety in advance of this work (15,24).Both CHIMs are designed as "infection models" with an endpoint of viremia and mild symptoms of dengue infection, including mild-moderate rash, transient neutropenia, and mild retro-orbital pain, all prevented by TV005 vaccination.In contrast, CHIM strains under development by other teams are designed as "disease models" and cause signs and symptoms consistent with classic dengue fever including fever and high viremia (19,25,26).We believe the protective effect of TV005 against infection and concomitant symptoms of rDENV2∆30 and rDENV3∆30 "infection models" are indicative of protection against wild-type dengue, and safe for human volunteers.The DENV2 component of the work herein builds on and confirms our previous evaluation of the NIH TV003 vaccine (15), which contains a 10-fold lower dosage of the DENV2 vaccine component (10 3 PFU) compared to TV005 (27).Both TV003 and TV005 protected all (100%) subjects from infection with rDENV2∆30.During the development of TV005, neutralization against parent virus strain targets provided an unbiased means of evaluating immunogenicity since it is possible to find target strains that yield either higher or lower titers compared to the actual parental strain (28).Nonetheless, we note that the DENV2 vaccine component strain (New Guinea C/1944 [an Asian II genotype]) elicited neutralizing antibodies against the American genotype Tonga/1974 challenge virus as well as other more recent strains (29).This work is an important milestone in the late stages of human testing of the TV003 and TV005 vaccines and adds to the data set a demonstration of safety and broad serotype immunogenicity of TV005, including in endemic settings (9,14,30).TV003 is being tested in ongoing phase III vaccine efficacy evaluations in Brazil.Two-year data suggests overall vaccine efficacy of 80% against the two circulating strains (DENV1, 90% and DENV2, 70%) (31).Notably, efficacy is not 100%, as is the case in CHIMs performed six months after vaccination (15).Multiple factors found in a real-world field trial can explain the lack of precision between the models, but do not diminish the power of the CHIM as an initial evaluation of vaccine efficacy.These factors include local burden/intensity of transmission, infection by mosquito rather than needle, time interval between vaccination and DENV exposure, repeated exposures, and circulating strains.Our continued understanding of these variables will improve dengue CHIMs.Critically, the absence of circulation of DENV3 and DENV4 serotypes in this phase 3 trial (and thus lack of serotype efficacy data) underscores the vital importance of CHIMs to test vaccines against these missing serotypes, such as DENV3.Our DENV4 challenge virus is currently under development.
The opportunities for DENV CHIMs as an integrated component of global dengue vaccine development are still being realized.Additional dengue serotypes and strains from different viral backgrounds have been described (25,26,32,33); each model has distinct features, including various degrees of viral titer (viremia) and clinical signs/symptoms.Of particular interest are opportunities for vaccine-CHIMs in dengue-endemic settings where documentation of efficacy in populations with varying degrees of baseline immunity would increase confidence before the large-scale introduction of dengue vaccines or phase 3 efficacy trials in new populations.TV005 DENV challenge models (DENV2 and DENV3) are ongoing in Dhaka, Bangladesh.As noted above, CHIMs may supply critical data to assess vaccine efficacy to serotypes that are not continuously circulating in a specific population.They may also be used to clinically interrogate specific viral infection and replication processes, especially those that occur very early after infection and are clinically unapparent in natural settings.This work has notable limitations and observations that are not yet explained.We observed a disconnect between viremia and reactogenicity in our DENV3 CHIM.The DENV3∆30 challenge was provided here at a 10 4 PFU dose and had a lower viremia than observed in the DENV2 CHIM (10 3 PFU).Conversely, despite low viremia, this DENV3 model has more reactogenicity (including rash) than seen in volunteers receiving the DENV2∆30 challenge strain.In addition, and possibly explained by innate immune responses, the higher dose (10 4 PFU) of DEN3∆30 infected only 85% of placebo recipients vs. 100% of those receiving the lower (10 3 PFU) dose in a previous trial (24,34).Planned work on cellular and innate immune contributions in these cohorts is hoped to clarify these observations.In addition, human infection models cannot fully replace field testing in phase III efficacy and phase IV post-licensure evaluation of a new tetravalent dengue vaccine.These models cannot represent all possible dengue strains (and their intra-serotype breadth), predict the duration of protection, nor expand the safety database through study of a large population.Our models were performed at six months after vaccination, which may not be comparable to efficacy trials which assess protection over multiple years.CHIM cannot ethically be used in children.However, as models, they offer significant advances to our understanding of the safety, immunogenicity, and efficacy of new dengue vaccines.Due to the infectivity of all four serotype components, TV005 provides homotypic neutralizing antibodies to all four serotypes, as well as cellular immune responses to non-structural proteins and has now been demonstrated to protect completely against both DENV3 and DENV2 challenge.

Methods
Two randomized, placebo-controlled vaccine-controlled human infection model (CHIM) clinical trials were performed using the NIH live attenuated tetravalent dengue vaccine admixture TV005, under protocols CIR 299 (study 1, DENV2) and CIR 309 (study 2, DENV3).Trials were conducted in Burlington, Vermont and Baltimore, Maryland using Good Clinical Practice standards.
A second measure of efficacy was presence of rash and/or neutropenia following the DENV2 or DENV3 viral challenges.Additional study objectives included detailed assessments of serologic responses (peak, geometric mean titers, change following viral challenge and comparison between studies) and viremia (i.e., frequency, magnitude (maximum titer), and duration).
Inclusion and exclusion criteria included generally healthy dengue-naïve male and non-pregnant females, ages 18-50.Subjects were enrolled following comprehensive screening.All were seronegative for HIV, Hepatitis B and C; had normal hematology and blood chemistry results; and were otherwise generally healthy as determined by history and physical exam.Women of reproductive age were required to use approved contraceptive methods for the duration of the study.
For both clinical trials, subjects were randomized 1:1 in eight blocks of 6.Each block contained 3 vaccine recipients and 3 placebo recipients.A master log of treatment assignments was maintained separately from study records and a sealed copy of the treatment assignments was given to the Data Safety Monitoring Board (DSMB) Executive Secretary.Investigators and all clinical staff remained blinded until all subjects in a treatment block reached study day 270.
Six months post receipt of either vaccination or placebo, all returning eligible subjects were challenged with either DEN2Δ30 at a dose of 10 3 PFU (study 1) or DEN3Δ30 at a dose of 10 4 PFU (study 2).After both vaccination/placebo administration and virus challenge, subjects returned for follow up every other day for 16 days, then at days 28, 56, 90, 180 and 360.Safety analysis was recorded up to 28 days post vaccination and challenge.All AEs were graded by severity and relatedness.Solicited AE included rash, retro-orbital pain and headache.As part of the safety evaluation, blood was obtained for CBC with differential measurement and alanine aminotransferase (ALT) at regular intervals post-vaccination and challenge.
Neutralizing antibody responses to all four DENV strains in TV005 and DEN2Δ30 were measured by 50% plaque reduction neutralization test (PRNT 50), as previously described (27).PRNTs were performed before vaccine/placebo and challenge and on days 28, 56, 90, 180 thereafter.The TV005 DENV2 vaccine component contains the prM and E genes from DENV2 New Guinea C/1944 Prototype strain (Asian II genotype), in which the original 1944 patient sera was inoculated into a monkey to generate a serum pool (provided by Leon Rosen) (35).This monkey serum was passaged two times in mosquito C6/36 cells and sequenced for generation of the cDNA to create the rDEN2/4Δ30 vaccine component.The DENV-2 NGC target virus was used in the PRNT assay is a passage 7 derivative of the original 1944 isolate (passaged in live monkey, C6/36, and Vero cells).The rDENV2∆30 Tonga/74 challenge strain an American genotype, is derived from two passages (p2) in C6/36 cells inoculated with patient serum from the 1974 outbreak in Tonga (provided by Duane Gubler) followed by sequence analysis to generate the cDNA to create the DENV2Δ30 challenge strain (GenBank AY44149).The DENV2 Tonga/74 target virus used in the PRTN is a passage 4 derivative of the original 1974 isolate (passaged in C6/36 and Vero cells) (20).DENV2 Tonga/74 has been shown to be more resistant to neutralization by serum from rDENV2∆30-infected persons compared to other genotypes (29).Both DENV2 wildtype strains (NGC and Tonga/74) were used as target viruses for the PRNT of serum post-vaccination and post DENV2∆30 challenge.The rDEN3∆30/31 Sleman/78 vaccine component and rDEN3∆30 Sleman/78 challenge strain are derived from two passages (p2) in C6/36 cells inoculated with patient serum from the 1978 outbreak in Indonesia (provided by Duane Gubler) (21) followed by sequence analysis to generate the cDNA to create the DENV3 Sleman/78 strains (Genbank accession AY656170).The rDEN3 Sleman/78 target virus used in the PRNT assay is a passage 5 derivative of the original 1978 isolate which was engineered from sequence derived from the C6/36 p2 isolate and subsequently passaged three times in C6/36 or Vero cells.Thus, the DENV3 vaccine strain, challenge strain, and PRNT target strain share antigenic homology, but differ in their attenuation phenotypes.Seropositivity was defined as a PRNT50 ≥10; seroconversion was defined as a four-fold or higher antibody titer compared to pre-vaccination (or prechallenge) titers.Batching of the assays was done separately, with assays run for the post-vaccine period separately from the post-CHIM period.We defined infection following challenge as the presence of viremia or seroconversion by day 90 post-challenge.
Statistics: A per-protocol analysis was performed.Fisher's Exact test was used to determine the protective efficacy of the vaccine after challenge with either DEN2Δ30 or DEN3Δ30 where viremia and rash in vaccine recipients were compared to placebo.Fisher's Exact test was used to determine statistically significant solicited adverse events in vaccinees compared to placebos.For immunogenicity analysis, peak geometric mean titers were calculated, and frequency of post-vaccine and post-challenge seropositivity was determined through day 90 following TV005/placebo and challenge, and frequency of challenge seroconversion through study day 90 post-challenge.Student's T-test was used to compare decline in clinical laboratory values.P values <0.05 are considered statistically significant.
Study approval: All research was approved by Institutional Review Boards at both universities.The TV005 vaccine and both viral challenge strains (DENV2, DENV3) were used under FDA Investigational New Drug applications (IND #15753).Informed consent was obtained from all subjects and human experimentation guidelines of the United States Department of Health and Human Services were followed in the conduct of human research.The percent decline in absolute neutrophil count, absolute lymphocyte count, and platelet count following vaccination with TV005 compared to placebo.All TV005-vaccinated participants (n=48) and placebo recipients (n=50) from both CIR299 and CIR309 were included in these analyses.The nadir in neutrophil, lymphocyte, and platelet count measured through study day 16 post-vaccination (or challenge) was compared to the value at study day 0 pre-vaccination (or pre-challenge).The percent decline was calculated as the absolute decline/baseline value*100.Individual data along with means and 95% confidence intervals are shown.Unpaired Student's T-test was used to compare TV005 vs. placebo.
A,B,C: Percent decline in the absolute neutrophil count (ANC, A), absolute lymphocyte count (ALC, B), absolute platelet count (C) postvaccination compared with value prior to vaccination (day 0) for volunteers who received TV005 vaccination or placebo.% decline was greater among TV005 participants compared to placebo (neutrophils and lymphocytes p<0.0001, platelets p=0.018)D,E,F: Percent decline in the absolute neutrophil count (ANC, D), absolute lymphocyte count (ALC, E), absolute platelet count (F) compared to day of viral challenge, in subjects who received TV005 or placebo and who subsequently (6 months later) all received DENV 2 viral challenge.Volunteers who received placebo (not TV005 vaccine) had significantly greater declines in neutrophils, lymphocytes, and platelets following DENV2 challenge compared with volunteers who received TV005 (p <0.0001).
G,H,I: Percent decline in the absolute neutrophil count (ANC, G), absolute lymphocyte count (ALC, H), absolute platelet count (I) compared to day of viral challenge, in subjects who received TV005 or placebo and who subsequently (6 months later) all received DENV 3 viral challenge.Volunteers who received placebo (not TV005 vaccine) had significantly greater declines in neutrophils, lymphocytes, and platelets following DENV3 challenge compared with volunteers who received TV005.(p <0.0001).10.

2 ,
adverse events following the DENV3 challenge predominated in the placebo group.

Figure 2 :
Figure 2: Decline in absolute lymphocyte count (ALC), absolute neutrophil count (ANC), and platelets following administration of TV005 and DENV2 or DENV3 challenge 6 months later.

Figure 3 :
Figure 3: Seroconversion to multiple serotypes following vaccination of dengue-naïve adult volunteers with TV005.

Figure 3
Figure 3 Legend: Following TV005 vaccination of adult dengue-naïve volunteers (Day ) and subsequent time points after vaccination, volunteers demonstrate seroconversion to one (monovalent) to four (tetravalent) serotypes.The majority of in study 1 (CIR299) or study 2 (CIR309) demonstrate seroconversion to all four (trivalent) serotypes.

Figure 4
Figure 4 Serum neutralizing antibody responses through Day 90 in TV005 vaccine or placebo recipients, following TV005 vaccination and subsequent DEVN2 or DEVN3 viral challenge.

Figure 4
Figure 4  Legend: Individual data are shown along with box and whisker plots; the box is the median with 25th and 75th percentiles; whiskers extend to minimum/maximum value, no further than 1.5 x IQR from the lower/ upper quartile.For DENV2 responses, all data shown postvaccination and challenge reflect responses to rDEN2/4Δ30 (NGC) strain.Responses to both the DENV2∆30 (NGC) and DENV2∆30 strain (Tonga) are shown in Table10.

Table 1 :
Demographics of study subjects vaccinated with the TV005 tetravalent dengue vaccine or placebo, followed by challenge with DENV2 or DENV3.

Table 2 :
Primary efficacy endpoint, frequency of viremia in vaccine or placebo recipients, following DENV2 or DENV3 challenge.

Table 3 :
Viremia by direct cell culture following TV005 vaccination or viral challenge (DENV2 or DENV3) of placebo recipients.

Table 10 :
Peak neutralizing antibody responses through Day 90 after vaccination and following viral challenge with DENV2 or DENV3, in TV005 vaccine or placebo recipients.