PhD Thesis Presentation-2017.pdf (original) (raw)
Related papers
A multifaceted approach to RSV vaccination
Human vaccines & immunotherapeutics, 2018
Respiratory Syncytial Virus (RSV) is the leading cause of pneumonia and bronchiolitis in infants, resulting in significant morbidity and mortality worldwide. In addition, RSV infections occur throughout different ages, thus, maintaining the virus in circulation, and increasing health risk to more susceptible populations such as infants, the elderly, and the immunocompromised. To date, there is no vaccine approved to prevent RSV infection or minimize symptoms of infection. Current clinical trials for vaccines against RSV are being carried out in four very different populations. There are vaccines that target two different pediatric populations, infants 2 to 6 month of age and seropositive children over 6 months of age, as well as women (non-pregnant or pregnant in their third trimester). There are vaccines that target adult and elderly populations. In this review, we will present and discuss RSV vaccine candidates currently in clinical trials. We will describe the preclinical studies...
Acta virologica, 2018
Development of potent vaccine for human respiratory syncytial virus (HRSV) that confers better protection than natural infection remains a global challenge. Vaccination with naked DNA is considered successful approach for the control of many viral diseases. In this study, the potential of DNA vaccination using full-length attachment gene of HRSV type A Saudi strain cloned in pcDNA3.1 + vector (pcDNA/GA) was evaluated in BALB/c mice. The expression efficiency of pcDNA/GA was first confirmed in HEp-2 cells on RNA and protein levels. Mice immunization with either pcDNA/GA or the positive control formalin-inactivated vaccine (FI-RSV) has generated significant serum antibody concentration in ELISA (7.31±0.418 and 9.76±0.006 µg/ml, respectively) with superior neutralizing activity. Similarly, both immunogens evoked robust HRSV-specific CD8+ T-cell response in ELISPOT assay compared to mice immunized with pcDNA3.1 + vector or saline (negative controls). Challenge of the immunized mice with the wild-type HRSV did not provoke clinical symptoms or mortality in any mice group. On the 7 th day post-challenge, mice were euthanized and lungs were extirpated for evaluation of viral load, histopathological changes and cytokine profile. A significant diminish in the viral load and histology score were concluded in lungs of pcDNA/GA immunized mice compared to those immunized with FI-RSV and negative controls. The pulmonary cytokine profile of pcDNA/GA immunized mice displayed notable upregulation of Th1-associated cytokines while that of FI-RSV immunized mice exhibited high levels of Th2-associated cytokines. In conclusion, the DNA vaccine candidate pcDNA/GA has proven prominent efficacy and safety in mouse model, which encourages further evaluation in clinical trials.
Vaccine, 2001
Objective: To explore whether RSV vaccines are efficacious in preventing respiratory syncytial virus (RSV) lower respiratory infection (LRI). Methods: Randomized clinical trials were sought through Medline using the following search terms: 'RSV' or 'RSV infection' and 'viral vaccine'. Randomized controlled trials in adults or children that provided data on clinical outcomes (RSV LRIs, all LRI, all RSV infections) were included. Control groups could receive placebo or another vaccine. Qualitative assessment and summary data were obtained independently by three authors and summarized on a pre-printed form. Where disagreements occurred, the studies were reviewed by all investigators. These disagreements were mainly clerical, such as misinterpretations of the table or text or transcription errors. Consensus was obtained for all studies. Summary statistics consists of relative risk (RR) and number needed to vaccinate to prevent the above outcomes. Results: Because of the outcomes examined, only studies of a purified F protein subunit (PFP) vaccine were included in the meta-analysis. These clinical trials were phase I studies to determine vaccine safety rather than efficacy. Efficacy of PFP-1 or PFP-2 vaccine were analyzed together. A statistically significant RR in overall number of RSV infections was observed RR 0.55 (95%CI, 0.35, 0.88), but the test of heterogeneity was significant raising doubts about the validity of this conclusion. The effect of vaccination on RSV LRI did not reach statistical significance. Conclusions: RSV subunit vaccines were found to reduce the overall incidence of all RSV infections. However, RSV subunit vaccines must be tested in large field trials because of concerns about the appropriateness of pooling, the risk of publication bias and the fact that the clinically important outcome of RSV LRI was not reduced.
The Journal of …, 2000
A live-attenuated, intranasal respiratory syncytial virus (RSV) candidate vaccine, cpts-248/ 404, was tested in phase 1 trials in 114 children, including 37 1-2-month-old infants-a target age for RSV vaccines. The cpts-248/404 vaccine was infectious at 104 and 105 plaque-forming units in RSV-naive children and was broadly immunogenic in children 16 months old. Serum and nasal antibody responses in 1-2 month olds were restricted to IgA, had a dominant response to RSV G protein, and had no increase in neutralizing activity. Nevertheless, there was restricted virus shedding on challenge with a second vaccine dose and preliminary evidence for protection from symptomatic disease on natural reexposure. The cpts-248/404 vaccine candidate did not cause fever or lower respiratory tract illness. In the youngest infants, however, cpts-248/404 was unacceptable because of upper respiratory tract congestion associated with peak virus recovery. A live attenuated RSV vaccine for the youngest infant will use cpts-248/404 modified by additional attenuating mutations. Respiratory syncytial virus (RSV) is the leading cause of severe viral respiratory disease in infants and children [1]. It is also an important cause of severe respiratory disease in the elderly [2], immunocompromised patients of all ages [3, 4], and infants with underlying cardiopulmonary disease [5]. It is considered a major infectious trigger for reactive airway disease [6]. RSV infections are estimated to account for ∼90,000 pediatric hospitalizations and 4500 deaths yearly in the United
Advances in RSV vaccine research and development – A global agenda
Vaccine, 2016
Highlights RSV is a significant annual cause of lower respiratory tract illness globally. Pediatric and elderly populations are most vulnerable, but no vaccine exists. The current state of RSV vaccine research and development is summarized. 60 RSV vaccine candidates in development, of which 16 are in Phase 1-3 trials.
New insights for development of a safe and protective RSV vaccine
Human Vaccines, 2010
Respiratory Syncytial Virus (RSV) is the leading cause of pneumonia and bronchiolitis in infants and children <1 year old, resulting in significant morbidity and mortality worldwide. There is currently no RSV vaccine. In the 1960's, a formalin-inactivated RSV (FI-RSV) vaccine trial led to exacerbated disease upon natural infection of vaccinees, including two deaths. The causes involved in the disastrous results of these vaccine trials are still unclear but they remain the engine for searching new avenues to develop a safe vaccine that can provide long-term protection against this important pathogen. This article reviews some of the early history of RSV vaccine development, as well as more recent information on the interaction between RSV and the host innate and adaptive immune responses. A safe and efficacious vaccine for RSV will require "re-education" of the host immune response against RSV to prevent vaccine-enhanced or severe RSV disease.
Journal of Infectious …, 2005
Background. Recombination technology can be used to create live attenuated respiratory syncytial virus (RSV) vaccines that contain combinations of known attenuating mutations. Methods. Two live attenuated, recombinantly derived RSV vaccine candidates, rA2cp248/404DSH and rA2cp248/404/1030DSH, were evaluated in 31 adults and in 95 children у6 months old. rA2cp248/404/1030DSH was subsequently evaluated in 44 infants 1-2 months old. These vaccine candidates share 4 attenuating genetic elements and differ only in a missense mutation (1030) in the polymerase gene. Results. Both vaccines were highly attenuated in adults and RSV-seropositive children and were well tolerated and immunogenic in RSV-seronegative children. Compared with that of rA2cp248/404DSH, replication of rA2cp248/404/1030DSH was restricted in RSV-seronegative children (mean peak titer, 10 4.3 vs. 10 2.5 plaque-forming units [pfu]/mL), indicating that the 1030 mutation had a potent attenuating effect. Although rA2cp248/404/ 1030DSH was well tolerated in infants, only 44% of infants who received two 10 5.3-pfu doses of vaccine had detectable antibody responses. However, replication after administration of the second dose was highly restricted, indicating that protective immunity was induced. At least 4 of 5 attenuating genetic elements were retained in recovered vaccine viruses. Conclusions. rA2cp248/404/1030DSH is the first RSV vaccine candidate to be sufficiently attenuated in young infants. Additional studies are needed to determine whether rA2cp248/404/1030DSH can induce protective immunity against wild-type RSV. Respiratory syncytial virus (RSV) is the most important cause of viral lower respiratory tract illness (LRI) in infants and children [1], but a vaccine is not available because of several obstacles, including the need to vaccinate early in life [2-4] and the history of immune-mediated enhancement of naturally occurring RSV disease among RSV-naive recipients of a formalininactivated RSV vaccine [5-7]. Enhanced RSV disease has never been observed after natural infection or ad
Live-attenuated Vaccines Prevent Respiratory Syncytial Virus–associated Illness in Young Children
American Journal of Respiratory and Critical Care Medicine, 2021
Rationale: Active immunization is needed to protect infants and young children against respiratory syncytial virus (RSV). Rationally designed live-attenuated RSV vaccines are in clinical development. Objectives: Develop preliminary estimates of vaccine efficacy, assess durability of antibody responses to vaccination and "booster" responses after natural RSV infection, and determine sample sizes needed for more precise estimates of vaccine efficacy. Methods: We analyzed data from seven phase 1 trials of live-attenuated RSV vaccines in 6-to 24-month-old children (n = 239). Measurements and Main Results: The five vaccine regimens that induced neutralizing antibody responses in >80% of vaccinees (defined post hoc as "more promising") protected against RSV-associated medically attended acute respiratory illness (RSV-MAARI) and medically attended acute lower respiratory illness (RSV-MAALRI) and primed for potent anamnestic responses upon natural exposure to wild-type RSV. Among recipients of "more promising" RSV vaccines, efficacy against RSV-MAARI was 67% (95% confidence interval [CI], 24 to 85; P = 0.008) and against RSV-MAALRI was 88% (95% CI, 29 to 99; P = 0.04). A greater than or equal to fourfold increase in RSV serum neutralizing antibody following vaccination was strongly associated with protection against RSV-MAARI (odds ratio, 0.26; 95% CI, 0.09 to 0.75; P = 0.014) and RSV-MAALRI; no child with a greater than or equal to fourfold increase developed RSV-MAALRI. Rates of RSV-MAARI and RSV-MAALRI in placebo recipients were 21% and 7%, respectively. Given these rates, a study of 540 RSV-naive children would have 90% power to demonstrate >55% efficacy against RSV-MAARI and >80% efficacy against RSV-MAALRI; if rates were 10% and 3%, a study of 1,300 RSV-naive children would be needed. Conclusions: Rapid development of a live-attenuated RSV vaccine could contribute substantially to reducing the global burden of RSV disease.