Safety and Immunogenicity of Ad26-Vectored HIV Vaccine With Mosaic Immunogens and a Novel Mosaic Envelope Protein in HIV-Uninfected Adults: A Phase 1/2a Study.

BACKGROUND: Developing a cross-clade, globally effective HIV vaccine remains crucial for eliminating HIV. METHODS: This placebo-controlled, double-blind, phase 1/2a study enrolled healthy HIV-uninfected adults at low risk for HIV infection. They were randomized (1:4:1) to receive 4 doses of an adenovirus 26-based HIV-1 vaccine encoding 2 mosaic Gag and Pol, and 2 mosaic Env proteins plus adjuvanted clade C gp140 (referred to here as clade C regimen), bivalent protein regimen (clade C regimen plus mosaic gp140), or placebo. Primary end points were safety and antibody responses. RESULTS: In total 152/155 participants (clade C, n = 26; bivalent protein, n = 103; placebo, n = 26) received ≥1 injection. The highest adverse event (AE) severity was grade 3 (local pain/tenderness, 12%, 2%, and 0% of the respective groups; solicited systemic AEs, 19%, 15%, 0%). HIV-1 mosaic gp140-binding antibody titers were 79 595 ELISA units (EU)/mL and 137 520 EU/mL in the clade C and bivalent protein groups (P < .001) after dose 4 and 16 862 EU/mL and 25 162 EU/mL 6 months later. Antibody response breadth against clade C gp140 and clade C/non-clade C gp120 was highest in the bivalent protein group. CONCLUSIONS: Adding mosaic gp140 to the clade C regimen increased and broadened the elicited immune response without compromising safety or clade C responses. Clinical Trials Registration. NCT02935686.

Central Nervous System Safety During Brief Analytic Treatment Interruption of Antiretroviral Therapy Within 4 Human Immunodeficiency Virus Remission Trials: An Observational Study in Acutely Treated People Living With Human Immunodeficiency Virus.

BACKGROUND: The central nervous system (CNS) is a likely reservoir of human immunodeficiency virus (HIV), vulnerable to viral rebound, inflammation, and clinical changes upon stopping antiretroviral therapy (ART). It is critical to evaluate the CNS safety of studies using analytic treatment interruption (ATI) to assess HIV remission. METHODS: Thirty participants who started ART during acute HIV infection underwent CNS assessments across 4 ATI remission trials. ART resumption occurred with plasma viral load >1000 copies/mL. CNS measures included paired pre- vs post-ATI measures of mood, cognitive performance, and neurologic examination, with elective cerebrospinal fluid (CSF) sampling, brain diffusion tensor imaging (DTI) and magnetic resonance spectroscopy (MRS). RESULTS: Median participant age was 30 years old and 29/30 were male. Participants' median time on ART before ATI was 3 years, and ATI lasted a median of 35 days. Post-ATI, there were no differences in median mood scores or neurologic findings and cognitive performance improved modestly. During ATI, a low level of CSF HIV-1 RNA was detectable in 6 of 20 participants with plasma viremia, with no group changes in CSF immune activation markers or brain DTI measures. Mild worsening was identified in post-ATI basal ganglia total choline MRS, suggesting an alteration in neuronal membranes. CONCLUSION: No adverse CNS effects were observed with brief, closely monitored ATI in participants with acutely treated HIV, except an MRS alteration in basal ganglia choline. Further studies are needed to assess CNS ATI safety in HIV remission trials, particularly for studies using higher thresholds to restart ART and longer ATI durations.

Safety and immunogenicity of two heterologous HIV vaccine regimens in healthy, HIV-uninfected adults (TRAVERSE): a randomised, parallel-group, placebo-controlled, double-blind, phase 1/2a study.

BACKGROUND: Bioinformatically designed mosaic antigens increase the breadth of HIV vaccine-elicited immunity. This study compared the safety, tolerability, and immunogenicity of a newly developed, tetravalent Ad26 vaccine with the previously tested trivalent formulation. METHODS: This randomised, parallel-group, placebo-controlled, double-blind, phase 1/2a study (TRAVERSE) was done at 11 centres in the USA and one centre in Rwanda. Eligible participants were adults aged 18 to 50 years, who were HIV-uninfected, healthy at screening based on their medical history and a physical examination including laboratory assessment and vital sign measurements, and at low risk of HIV infection in the opinion of study staff, who applied a uniform definition of low-risk guidelines that was aligned across sites. Enrolled participants were randomly assigned at a 2:1 ratio to tetravalent and trivalent groups. Participants in tetravalent and trivalent groups were then further randomly assigned at a 5:1 ratio to adenovirus 26 (Ad26)-vectored vaccine and placebo subgroups. Randomisation was stratified by region (USA and Rwanda) and based on a computer-generated schedule using randomly permuted blocks prepared under the sponsor's supervision. We masked participants and investigators to treatment allocation throughout the study. On day 0, participants received a first injection of tetravalent vaccine (Ad26.Mos4.HIV or placebo) or trivalent vaccine (Ad26.Mos.HIV or placebo), and those injections were repeated 12 weeks later. At week 24, vaccine groups received a third dose of tetravalent or trivalent together with clade C gp140, and this was repeated at week 48, with placebos again administered to the placebo group. All study vaccines and placebo were administered by intramuscular injection in the deltoid muscle. We assessed adverse events in all participants who received at least one study injection (full analysis set) and Env-specific binding antibodies in all participants who received at least the first three vaccinations according to the protocol-specified vaccination schedule, had at least one measured post-dose blood sample collected, and were not diagnosed with HIV during the study (per-protocol set). This study is registered with Clinicaltrials.gov, NCT02788045. FINDINGS: Of 201 participants who were enrolled and randomly assigned, 198 received the first vaccination: 110 were in the tetravalent group, 55 in the trivalent group, and 33 in the placebo group. Overall, 185 (93%) completed two scheduled vaccinations per protocol, 180 (91%) completed three, and 164 (83%) completed four. Solicited, self-limiting local, systemic reactogenicity and unsolicited adverse events were similar in vaccine groups and higher than in placebo groups. All participants in the per-protocol set developed clade C Env binding antibodies after the second vaccination, with higher total IgG titres after the tetravalent vaccine than after the trivalent vaccine (10 413 EU/mL, 95% CI 7284-14 886 in the tetravalent group compared with 5494 EU/mL, 3759-8029 in the trivalent group). Titres further increased after the third and fourth vaccinations, persisting at least through week 72. Other immune responses were also higher with the tetravalent vaccine, including the magnitude and breadth of binding antibodies against a cross-clade panel of Env antigens, and the magnitude of IFNγ ELISPOT responses (median 521 SFU/106 peripheral blood mononuclear cells [PBMCs] in the tetravalent group and median 282 SFU/106 PBMCs in the trivalent group after the fourth vaccination) and Env-specific CD4+ T-cell response rates after the third and fourth vaccinations. No interference by pre-existing Ad26 immunity was identified. INTERPRETATION: The tetravalent vaccine regimen was generally safe, well-tolerated, and found to elicit higher immune responses than the trivalent regimen. Regimens that use this tetravalent vaccine component are being advanced into field trials to assess efficacy against HIV-1 infection. FUNDING: National Institutes of Health, Henry M Jackson Foundation for Advancement of Military Medicine and the US Department of Defense, Ragon Institute of MGH, MIT, & Harvard, Bill & Melinda Gates Foundation, and Janssen Vaccines & Prevention.

Long-term antibody persistence in children after vaccination with the pediatric formulation of an aluminum-free virosomal hepatitis A vaccine.

BACKGROUND: The pediatric dose of the virosomal hepatitis A vaccine Epaxal, Epaxal Junior, is safe and immunogenic in children from 1 to 17 years of age. The present study investigated the long-term immunogenicity of Epaxal Junior. The standard doses of Epaxal and aluminum-adsorbed hepatitis A vaccine (Havrix Junior) were used as comparators. METHODS: A total of 271 children who had completed a 0/6-month immunization schedule (priming and booster dose) participated in this follow-up study. Anti-hepatitis A virus (HAV) antibody levels were measured using a microparticle enzyme immunoassay (HAVAB 2.0 Quantitative; Abbott Diagnostics, Wiesbaden, Germany) starting at 18 months following the second dose, and then yearly until 66 months (ie, 5.5 years) after the second dose. RESULTS: All subjects tested at Month 66 still had protective anti-HAV antibodies (≥10 mIU/mL). Antibody titers were generally lower in subjects 1-7 years old than in subjects 8-17 years old and higher in females 11-17 years old than in males 11-17 years old. In addition, an age-dependent decay was observed, that is, antibody decreased more rapidly in younger than in older children. CONCLUSIONS: Vaccination of children with two doses of Epaxal Junior confers a real-time protection of at least 5.5 years. This protection is estimated to last approximately 25 years. Younger children showed lower antibody titers and a faster antibody decline than older children. Additional follow-up studies are needed beyond 5.5 years to further assess the long-term immunogenicity of Epaxal Junior.