ISV Paper of the Year, 2014
Clinical efficacy and safety of a novel tetravalent dengue vaccine in healthy children in Asia: a phase 3, randomised, observer-masked, placebo-controlled trial
The Lancet. 2014. 384:1358-1365
Maria Rosario Capeding, Ngoc Huu Tran, Sri Rezeki S Hadinegoro, Hussain Imam HJ Muhammad Ismail, Tawee Chotpitayasunondh, Mary Noreen Chua, Chan Quang Luong, Kusnandi Rusmil, Dewa Nyoman Wirawan, Revathy Nallusamy, Punnee Pitisuttithum, Usa Thisyakorn, In-Kyu Yoon, Diane van der Vliet, Edith Langevin, Thelma Laot, Yanee Hutagalung, Carina Frago, Mark Boaz, T Anh Wartelo, Nadia G Tornieporth, Melanie Saville, Alain Bouckenooghe and the CYD14 Study Group.
An estimated 100 million people have symptomatic dengue infection every year. This is the first report of a phase 3 vaccine efficacy trial of a candidate dengue vaccine. We aimed to assess the efficacy of the CYD dengue vaccine against symptomatic, virologically confirmed dengue in children.
We did an observer-masked, randomised controlled, multicentre, phase 3 trial in five countries in the Asia-Pacific region. Between June 3, and Dec 1, 2011, healthy children aged 2–14 years were randomly assigned (2:1), by computer-generated permuted blocks of six with an interactive voice or web response system, to receive three injections of a recombinant, live, attenuated, tetravalent dengue vaccine (CYD-TDV), or placebo, at months 0, 6, and 12. Randomisation was stratified by age and site. Participants were followed up until month 25. Trial staff responsible for the preparation and administration of injections were unmasked to group allocation, but were not included in the follow-up of the participants; allocation was concealed from the study sponsor, investigators, and parents and guardians. Our primary objective was to assess protective efficacy against symptomatic, virologically confirmed dengue, irrespective of disease severity or serotype, that took place more than 28 days after the third injection. The primary endpoint was for the lower bound of the 95% CI of vaccine efficacy to be greater than 25%. Analysis was by intention to treat and per procotol. This trial is registered with ClinicalTrials.gov, number NCT01373281.
We randomly assigned 10 275 children to receive either vaccine (n=6851) or placebo (n=3424), of whom 6710 (98%) and 3350 (98%), respectively, were included in the primary analysis. 250 cases of virologically confirmed dengue took place more than 28 days after the third injection (117 [47%] in the vaccine group and 133 [53%] in the control group). The primary endpoint was achieved with 56·5% (95% CI 43·8–66·4) efficacy. We recorded 647 serious adverse events (402 [62%] in the vaccine group and 245 [38%] in the control group). 54 (1%) children in the vaccine group and 33 (1%) of those in the control group had serious adverse events that happened within 28 days of vaccination. Serious adverse events were consistent with medical disorders in this age group and were mainly infections and injuries.
Our findings show that dengue vaccine is efficacious when given as three injections at months 0, 6, and 12 to children aged 2–14 years in endemic areas in Asia, and has a good safety profile. Vaccination could reduce the incidence of symptomatic infection and hospital admission and has the potential to provide an important public health benefit.
ISV Paper of the Year, 2013
Structure-Based Design of a Fusion Glycoprotein Vaccine for Respiratory Syncytial Virus
Science. 2013. Vol. 342, p. 592
McLellan JS, Chen M, Gordon Joyce M, Sastry M, Stewart-Jones GBE, Yang Y, Zhang B, Chen L, Srivatsan S, Zheng A, Zhou T, Graepel KW, Kumar A, Moin S, Boyington JC, Chuang G-Y, Soto C, Baxa U, Bakker AQ, Spits H, Beaumont T, Zheng Z, Xia N, Ko S-Y, Todd J-P, Rao S, Graham BS, Kwong PD.
Respiratory syncytial virus (RSV) is the leading cause of hospitalization for children under 5 years of age. We sought to engineer a viral antigen that provides greater protection than currently available vaccines and focused on antigenic site Ø, a metastable site specific to the prefusion state of the RSV fusion (F) glycoprotein, as this site is targeted by extremely potent RSV-neutralizing antibodies. Structure-based design yielded stabilized versions of RSV F that maintained antigenic site Ø when exposed to extremes of pH, osmolality, and temperature. Six RSV F crystal structures provided atomic-level data on how introduced cysteine residues and filled hydrophobic cavities improved stability. Immunization with site Ø–stabilized variants of RSV F in mice and macaques elicited levels of RSV-specific neutralizing activity many times the protective threshold.
ISV Paper of the Year, 2012
Immune-correlates analysis of an HIV-1 vaccine efficacy trial.
New England Journal of Medicine. 2012. 366(14):1275-1286.
Haynes BF, Gilbert PB, McElrath MJ, Zolla-Pazner S, Tomaras GD, Alam SM, Evans DT, Montefiori DC, Karnasuta C, Sutthent R, Liao HX, DeVico AL, Lewis GK, Williams C, Pinter A, Fong Y, Janes H, DeCamp A, Huang Y, Rao M, Billings E, Karasavvas N, Robb ML, Ngauy V, de Souza MS, Paris R, Ferrari G, Bailer RT, Soderberg KA, Andrews C, Berman PW, Frahm N, De Rosa SC, Alpert MD, Yates NL, Shen X, Koup RA, Pitisuttithum P, Kaewkungwal J, Nitayaphan S, Rerks-Ngarm S, Michael NL, Kim JH.
In the RV144 trial, the estimated efficacy of a vaccine regimen against human immunodeficiency virus type 1 (HIV-1) was 31.2%. We performed a case-control analysis to identify antibody and cellular immune correlates of infection risk.
In pilot studies conducted with RV144 blood samples, 17 antibody or cellular assays met prespecified criteria, of which 6 were chosen for primary analysis to determine the roles of T-cell, IgG antibody, and IgA antibody responses in the modulation of infection risk. Assays were performed on samples from 41 vaccinees who became infected and 205 uninfected vaccinees, obtained 2 weeks after final immunization, to evaluate whether immune-response variables predicted HIV-1 infection through 42 months of follow-up.
Of six primary variables, two correlated significantly with infection risk: the binding of IgG antibodies to variable regions 1 and 2 (V1V2) of HIV-1 envelope proteins (Env) correlated inversely with the rate of HIV-1 infection (estimated odds ratio, 0.57 per 1-SD increase; P=0.02; q=0.08), and the binding of plasma IgA antibodies to Env correlated directly with the rate of infection (estimated odds ratio, 1.54 per 1-SD increase; P=0.03; q=0.08). Neither low levels of V1V2 antibodies nor high levels of Env-specific IgA antibodies were associated with higher rates of infection than were found in the placebo group. Secondary analyses suggested that Env-specific IgA antibodies may mitigate the effects of potentially protective antibodies.
This immune-correlates study generated the hypotheses that V1V2 antibodies may have contributed to protection against HIV-1 infection, whereas high levels of Env-specific IgA antibodies may have mitigated the effects of protective antibodies. Vaccines that are designed to induce higher levels of V1V2 antibodies and lower levels of Env-specific IgA antibodies than are induced by the RV144 vaccine may have improved efficacy against HIV-1 infection.
ISV Paper of the Year, 2011
Systems Bology of Seasonal Influenza Vaccinations in Humans
Nat Immunol. 2011 Jul 10;12(8):786-95
Helder I Nakaya, Jens Wrammert, Eva K Lee, Luigi Racioppi, Stephanie Marie-Kunze, W Nicholas Haining, Anthony R Means, Sudhir P Kasturi, Nooruddin Khan, Gui-Mei Li, Megan McCausland, Vibhu Kanchan, Kenneth E Kokko, Shuzhao Li, Rivka Elbein, Aneesh K Mehta, Alan Aderem, Kanta Subbarao, Rafi Ahmed & Bali Pulendran.
We used a systems biological approach to study innate and adaptive responses to influenza vaccination in humans, during 3 consecutive influenza seasons. Healthy adults were vaccinated with inactivated (TIV) or live attenuated (LAIV) influenza vaccines. TIV induced greater antibody titers and enhanced numbers of plasmablasts than LAIV. In TIV vaccinees, early molecular signatures correlated with, and accurately predicted, later antibody titers in two independent trials. Interestingly, the expression of Calcium/calmodulin-dependent kinase IV (CamkIV) at day 3 was inversely correlated with later antibody titers. Vaccination of CamkIV −/− mice with TIV induced enhanced antigen-specific antibody titers, demonstrating an unappreciated role for CaMKIV in the regulation of antibody responses. Thus systems approaches can predict immunogenicity, and reveal new mechanistic insights about vaccines.
ISV Nomination Statement:
A major challenge in vaccinology is that the effectiveness of vaccination can only be ascertained after vaccinated individuals have been exposed to infection. In 2009, Bali Pulendran and colleagues pioneered the use of a systems biological approach to study the global picture of the immune response to one of the most successful human vaccines ever developed, the live attenuated vaccine against yellow fever (Nat Immunol. 2009 Jan;10(1):116-25). Using this approach the investigators were able to identify signatures of gene expression in the blood of healthy humans, a few days after vaccination that could predict with up to 90 percent accuracy the strength of the immune response, weeks or months after yellow fever vaccination. In this ISV Paper of the Year (Nat Immunol. 2011 Jul 10;12(8):786-95), the same group, in collaboration with the group of Rafi Ahmed (an ISV member) and colleagues, now extend this approach to the seasonal influenza vaccines over the course of three influenza seasons. By studying gene expression patterns in the blood a few days after vaccination, the investigators were able to identify “signatures” that were capable of predicting the magnitude of the later immune response, with >90% accuracy. Importantly one of the genes in the signature, CAMK4 whose expression was negatively correlated with antibody titers, revealed an unappreciated role for CAMK4 in B cell responses. This landmark study, together with the previous work from the same group, demonstrates the use of systems biological approaches in predicting vaccine efficacy, and highlights one of the ways for the future of vaccinology - use of systems biology tools to perform sophisticated human studies that gives specific hypothesis to be tested experimentally