Search

Background Respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory illness among young children. Human immunodeficiency virus (HIV)–exposed, uninfected (HEU) children experience a higher burden of RSV disease and have immune abnormalities that may influence their responses to live-attenuated RSV vaccines. Methods In a pooled analysis of clinical trials of 7 live-attenuated, intranasal RSV vaccines conducted by the IMPAACT Network among children 6 to <25 months of age with serum RSV-neutralizing titers of <1:40, the infectivity and immunogenicity of these vaccines were compared among HEU and HIV-unexposed, uninfected (HUU) children. Nasal washes were collected during the first 28 days after vaccination. Serum RSV-neutralizing and anti-RSV F glycoprotein immunoglobulin G (IgG) antibodies were measured prior to and 56 days after vaccination, and before and after the following winter season. Results Of 156 children, 90 (58%) were HUU and 66 (42%) were HEU. Seventy-six (84%) HUU and 63 (95%) HEU participants were infected with vaccine (shed vaccine virus and/or had a ≥4-fold rise in serum RSV antibodies at 56 days after vaccination). HUU children had higher serum RSV-neutralizing and anti-RSV F IgG titers prior to vaccination. Compared to HEU children, lower percentages of HUU children had ≥4-fold rises in RSV-neutralizing (67% vs 88%) and anti-RSV F IgG (70% vs 89%) titers at 56 days after vaccination. Conclusions Live-attenuated RSV vaccines are highly immunogenic in HEU children. Given their increased burden of RSV disease and higher early childhood mortality in some settings, HEU children should be prioritized for vaccination against RSV as these vaccines become available. [ABSTRACT FROM AUTHOR]

Background Respiratory syncytial virus (RSV) is the leading cause of pediatric lower respiratory illness (LRI) and a vaccine for immunization of children is needed. RSV/6120/ΔNS2/1030s is a cDNA-derived live-vaccine candidate attenuated by deletion of the interferon antagonist NS2 gene and the genetically stabilized 1030s missense polymerase mutation in the polymerase, conferring temperature sensitivity. Methods A single intranasal dose of RSV/6120/ΔNS2/1030s was evaluated in a double-blind, placebo-controlled trial (vaccine to placebo ratio, 2:1) at 105.7 plaque-forming units (PFU) in 15 RSV-seropositive 12- to 59-month-old children, and at 105 PFU in 30 RSV-seronegative 6- to 24-month-old children. Results RSV/6120/ΔNS2/1030s infected 100% of RSV-seronegative vaccinees and was immunogenic (geometric mean RSV plaque-reduction neutralizing antibody titer [RSV-PRNT], 1:91) and genetically stable. Mild rhinorrhea was detected more frequently in vaccinees (18/20 vaccinees vs 4/10 placebo recipients, P =.007), and LRI occurred in 1 vaccinee during a period when only vaccine virus was detected. Following the RSV season, 5 of 16 vaccinees had ≥4-fold rises in RSV-PRNT with significantly higher titers than 4 of 10 placebo recipients with rises (1:1992 vs 1:274, P =.02). Thus, RSV/6120/ΔNS2/1030s primed for substantial anamnestic neutralizing antibody responses following naturally acquired RSV infection. Conclusions RSV/6120/ΔNS2/1030s is immunogenic and genetically stable in RSV-seronegative children, but the frequency of rhinorrhea in vaccinees exceeded that in placebo recipients. Clinical Trials Registration NCT03387137. [ABSTRACT FROM AUTHOR]

We conducted a phase I clinical trial of the live-attenuated recombinant human parainfluenza virus type 2 (HPIV2) vaccine candidate rHPIV2-15C/948L/∆1724 sequentially in adults, HPIV2-seropositive children, and HPIV2-seronegative children, the target population for vaccination. rHPIV2-15C/948L/∆1724 was appropriately restricted in replication in adults and HPIV2-seropositive children but was overattenuated for HPIV2-seronegative children. [ABSTRACT FROM AUTHOR]

Background Respiratory syncytial virus (RSV) is the leading global cause of severe pediatric acute respiratory tract illness, and a vaccine is needed. RSV/ΔNS2/Δ1313/I1314L contains 2 attenuating elements: (1) deletion of the interferon antagonist NS2 gene and (2) deletion of codon 1313 of the RSV polymerase gene and the stabilizing missense mutation I1314L. This live vaccine candidate was temperature-sensitive, genetically stable, replication restricted, and immunogenic in nonhuman primates. Methods A single intranasal dose of RSV/ΔNS2/Δ1313/I1314L was evaluated in a double-blind, placebo-controlled trial (vaccine-placebo ratio, 2:1) at 106 plaque-forming units (PFU) in 15 RSV-seropositive children and at 105 and 106 PFU in 21 and 30 RSV-seronegative children, respectively. Results In RSV-seronegative children, the 105 PFU dose was overattenuated, but the 106 PFU dose was well tolerated, infectious (RSV/ΔNS2/Δ1313/I1314L replication detected in 90% of vaccinees), and immunogenic (geometric mean serum RSV plaque-reduction neutralizing antibody titer, 1:64). After the RSV season, 9 of 20 vaccinees had increases in the RSV titer that were significantly greater than those in 8 of 10 placebo recipients (1:955 vs 1:69, respectively), indicating that the vaccine primed for anamnestic responses after natural RSV exposure. Conclusion Rational design yielded a genetically stable candidate RSV vaccine that is attenuated yet immunogenic in RSV-seronegative children, warranting further evaluation. Clinical Trials Registration NCT01893554. [ABSTRACT FROM AUTHOR]

Background Respiratory syncytial virus (RSV) is the leading viral cause of severe pediatric respiratory illness, and vaccines are needed. Live RSV vaccine D46/NS2/N/ΔM2-2-HindIII, attenuated by deletion of the RSV RNA regulatory protein M2-2, is based on previous candidate LID/ΔM2-2 but incorporates prominent differences from MEDI/ΔM2-2, which was more restricted in replication in phase 1. Methods RSV-seronegative children aged 6–24 months received 1 intranasal dose (105 plaque-forming units [PFUs] of D46/NS2/N/ΔM2-2-HindIII [n = 21] or placebo [n = 11]) and were monitored for vaccine shedding, reactogenicity, RSV-antibody responses and RSV-associated medically attended acute respiratory illness (RSV-MAARI) and antibody responses during the following RSV season. Results All 21 vaccinees were infected with vaccine; 20 (95%) shed vaccine (median peak titer, 3.5 log10 PFUs/mL with immunoplaque assay and 6.1 log10 copies/mL with polymerase chain reaction). Serum RSV-neutralizing antibodies and anti-RSV fusion immunoglobulin G increased ≥4-fold in 95% and 100% of vaccines, respectively. Mild upper respiratory tract symptoms and/or fever occurred in vaccinees (76%) and placebo recipients (18%). Over the RSV season, RSV-MAARI occurred in 2 vaccinees and 4 placebo recipients. Three vaccinees had ≥4-fold increases in serum RSV-neutralizing antibody titers after the RSV season without RSV-MAARI. Conclusions D46/NS2/N/ΔM2-2-HindIII had excellent infectivity and immunogenicity and primed vaccine recipients for anamnestic responses, encouraging further evaluation of this attenuation strategy. Clinical Trials Registration NCT03102034 and NCT03099291. [ABSTRACT FROM AUTHOR]

Background: Respiratory syncytial virus (RSV) is the most important viral cause of severe respiratory illness in young children and lacks a vaccine. RSV cold-passage/stabilized 2 (RSVcps2) is a modification of a previously evaluated vaccine candidate in which 2 major attenuating mutations have been stabilized against deattenuation.Methods: RSV-seronegative 6-24-month-old children received an intranasal dose of 105.3 plaque-forming units (PFU) of RSVcps2 (n = 34) or placebo (n = 16) (International Maternal Pediatric Adolescent AIDS Clinical Trials protocol P1114 and companion protocol CIR285). RSV serum neutralizing antibody titers before and 56 days after vaccination, vaccine virus infectivity (defined as vaccine virus shedding detectable in nasal wash and/or a ≥4-fold rise in serum antibodies), reactogenicity, and genetic stability were assessed. During the following RSV transmission season, participants were monitored for respiratory illness, with serum antibody titers measured before and after the season.Results: A total of 85% of vaccinees were infected with RSVcps2 (median peak titer, 0.5 log10 PFU/mL by culture and 2.9 log10 copies/mL by polymerase chain reaction analysis); 77% shed vaccine virus, and 59% developed a ≥4-fold rise in RSV-serum neutralizing antibody titers. Respiratory tract and/or febrile illness occurred at the same rate (50%) in the vaccine and placebo groups. Deattenuation was not detected at either of 2 stabilized mutation sites.Conclusions: RSVcps2 was well tolerated and moderately immunogenic and had increased genetic stability in 6-24-month-old RSV-seronegative children.Clinical Trials Registration: NCT01852266 and NCT01968083. [ABSTRACT FROM AUTHOR]

Background: Live respiratory syncytial virus (RSV) candidate vaccine LIDΔM2-2 is attenuated by deletion of the RSV RNA regulatory protein M2-2, resulting in upregulated viral gene transcription and antigen expression but reduced RNA replication.Methods: RSV-seronegative children ages 6-24 months received a single intranasal dose of 105 plaque forming units (PFU) of LIDΔM2-2 (n = 20) or placebo (n = 9) (NCT02237209, NCT02040831). RSV serum antibodies, vaccine infectivity, and reactogenicity were assessed. During the following RSV season, participants were monitored for respiratory illness and pre- and post-RSV season serum antibodies.Results: Vaccine virus was shed by 95% of vaccinees (median peak titers of 3.8 log10 PFU/mL by quantitative culture and 6.3 log10 copies/mL by PCR); 90% had ≥4-fold rise in serum neutralizing antibodies. Respiratory symptoms and fever were common in vaccine (95%) and placebo (78%). One vaccinee had grade 2 rhonchi concurrent with vaccine shedding, rhinovirus, and enterovirus. Eight of 19 vaccinees versus 2 of 9 placebo recipients had substantially increased RSV antibody titers after the RSV season without medically attended RSV disease, indicating anamnestic vaccine responses to wild-type RSV without significant illness.Conclusion: LIDΔM2-2 had excellent infectivity and immunogenicity, encouraging further study of vaccine candidates attenuated by M2-2 deletion.Clinical Trials Registration: NCT02237209, NCT02040831. [ABSTRACT FROM AUTHOR]

We conducted a phase I clinical trial of an experimental live attenuated recombinant human metapneumovirus (HMPV) vaccine (rHMPV-Pa) sequentially in adults, HMPV-seropositive children, and HMPV-seronegative children, the target population for vaccination. rHMPV-Pa was appropriately restricted in replication in adults and HMPV-seropositive children but was overattenuated for HMPV-seronegative children. [ABSTRACT FROM AUTHOR]

We conducted a phase I clinical trial (clinicaltrials.gov identifier, NCT00641017) of the experimental live-attenuated human parainfluenza virus type 1 (HPIV-1) vaccine rHPIV-1/84/del 170/942A sequentially in 3 groups: adults, HPIV-1-seropositive children, and HPIV-1-seronegative children, the target population for vaccination. rHPIV-1/84/del 170/942A was appropriately restricted in replication in adults and HPIV-1-seropositive children but was overattenuated (ie, insufficiently infectious and immunogenic) for HPIV-1-seronegative children. [ABSTRACT FROM AUTHOR]

Background. Human metapneumovirus (HMPV) causes lower respiratory tract infections in young children. rHMPV-SHs is a recombinant HMPV (rHMPV) based on a biologically derived wild-type HMPV strain. We characterized its infectivity and immunogenicity in healthy adults to determine whether it would be suitable for use as the parent virus for the development of live attenuated rHMPV vaccines.Methods. Twenty-one healthy adults were inoculated intranasally with 106 plaque-forming units of rHMPV-SHs. Respiratory symptoms and shedding of challenge virus were assessed. Neutralizing antibody responses, serum immunoglobulin G and A, and nasal wash specimen immunoglobulin A antibody responses to the HMPV F protein were also measured. Induction of nasal cytokines was assessed with electrochemiluminescence assays.Results. Nine subjects (43%) were infected with challenge virus as determined by virus detection and/or ≥4-fold rise in serum antibody titers. Peak viral shedding occurred on days 7–9 after infection. Four weeks after inoculation, 35% of subjects had any antibody response. Six of 9 infected subjects had respiratory symptoms, and 3 had headache after inoculation. Cytokine patterns differed considerably between subjects with similar illness severity and viral shedding.Conclusions. The rHMPV-SHs virus is infectious and is a suitable parent virus for development of live-attenuated HMPV vaccine candidates.Clinical Trials Registration. NCT01109329. [ABSTRACT FROM AUTHOR]

Background. Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract illness (LRTI) in children. Several promising live-attenuated RSV vaccines are in development. Defining additional markers of attenuation could enhance clinical trials.Methods. We used clinical data, virologic data, and nasal wash (NW) specimens from 20 RSV-naive children enrolled in studies of 4 live-attenuated RSV vaccines. Seven received minimally attenuated cpts248/955 or cpts530/1009 (group 1), 6 received moderately attenuated cpts248/404 (group 2), and 7 received highly attenuated rA2cp248/404/1030/ΔSH (group 3). NW specimens were tested for cytokines and chemokines via an electrochemiluminescence biosensor assay.Results. Group 1 exhibited 1 instance of LRTI and significantly higher rates of fever than groups 2 or 3; there were no significant differences in peak titers of vaccine virus in NW specimens. In contrast, levels of interferon γ, interleukin 1β, interleukin 2, interleukin 6, and interleukin 13 were significantly greater in NW specimens from group 1, compared with those from group 3. Maximum increases in levels of most cytokines occurred after peak viral replication but coincided with clinical illness.Conclusions. Substantial increases in proinflammatory, antiinflammatory, T-helper 1, T-helper 2, and regulatory cytokines were detected in children who received minimally attenuated live RSV vaccines but not in children who received highly attenuated vaccines. Levels of cytokines in NW specimens may be useful biomarkers of attenuation for live RSV vaccines. [ABSTRACT FROM AUTHOR]

Background In people over 65, there are on average 177,000 hospitalizations and 14,000 deaths because of respiratory syncytial virus (RSV) each year. Elderly patients infected with RSV can suffer serious infections leading to pneumonia and congestive heart failure. RSV vaccines have failed in the elderly in part because they have been unable to mount a robust cellular immune response. Methods RSV-MinL4.0 is a live-attenuated intranasal vaccine candidate that was generated by codon pair deoptimization of the L gene followed by the addition of four stabilizing mutations found via stress passaging. Four African Green Monkeys (AGMs) per group were vaccinated with RSV-MinL4.0 or wild-type (WT) RSV at 2 × 106 PFU, boosted on day 28 and challenged with wild-type (WT) RSV on day 104. Oropharyngeal swabs and tracheal lavage were collected daily and every other day, respectively, to evaluate virus shedding (qPCR) and blood was drawn on days 1, 14, 21, 28, and 49 for antibody titers (PRNT50), and PBMC activation (IFNγ ELISPOT with whole inactivated virus). Results MinL4.0 was 2 to 3 log10 attenuated when compared with WT RSV in AGMs. Despite the presence of antibodies on day 28, there was a "take" of the boost indicating the potential for this vaccine to be immunogenic in the elderly with pre-existing circulating antibodies (Figure 1A). MinL4.0 led to robust activation of PBMCs comparable to WT RSV (> 2,000 spots per 106 total cells, Figure 1B). Shedding of the vaccine and challenge viruses was minimal (data not shown). Conclusion MinL4.0 led to robust activation of cellular and humoral immune responses, which are critical for induction of protective immunity in the elderly. Animals were protected from WT challenge. Preliminary data in AGMs with pre-existing antibodies to RSV indicate that circulating antibodies do not prevent vaccine "take," critical for a vaccine targeting sero-positive elderly individuals. Disclosures All authors: No reported disclosures. [ABSTRACT FROM AUTHOR]