Safety, tolerability, and immunogenicity of the Ebola Sudan chimpanzee adenovirus vector vaccine (cAd3-EBO S) in healthy Ugandan adults: a phase 1, open-label, dose-escalation clinical trial.

BACKGROUND: Sudan Ebola virus can cause severe viral disease, with an average case fatality rate of 54%. A recent outbreak of Sudan Ebola virus in Uganda caused 55 deaths among 164 confirmed cases in the second half of 2022. Although vaccines and therapeutics specific for Zaire Ebola virus have been approved for use during outbreak situations, Sudan Ebola virus is an antigenically distinct virus with no approved vaccines available. METHODS: In this phase 1, open-label, dose-escalation trial we evaluated the safety, tolerability, and immunogenicity of a monovalent chimpanzee adenovirus 3 vaccine against Sudan Ebola virus (cAd3-EBO S) at Makerere University Walter Reed Project in Kampala, Uganda. Study participants were recruited from the Kampala metropolitan area using International Review Board-approved written and electronic media explaining the trial intervention. Healthy adults without previous receipt of Ebola, Marburg, or cAd3 vectored-vaccines were enrolled to receive cAd3-EBO S at either 1 × 1010 or 1 × 1011 particle units (PU) in a single intramuscular vaccination and were followed up for 48 weeks. Primary safety and tolerability endpoints were assessed in all vaccine recipients by reactogenicity for the first 7 days, adverse events for the first 28 days, and serious adverse events throughout the study. Secondary immunogenicity endpoints included evaluation of binding antibody and T-cell responses against the Sudan Ebola virus glycoprotein, and neutralising antibody responses against the cAd3 vector at 4 weeks after vaccination. This study is registered with ClinicalTrials.gov, NCT04041570, and is completed. FINDINGS: 40 healthy adults were enrolled between July 22 and Oct 1, 2019, with 20 receiving 1 × 1010 PU and 20 receiving 1 × 1011 PU of cAd3-EBO S. 38 (95%) participants completed all follow-up visits. The cAd3-EBO S vaccine was well tolerated with no severe adverse events. The most common reactogenicity symptoms were pain or tenderness at the injection site (34 [85%] of 40), fatigue (29 [73%] of 40), and headache (26 [65%] of 40), and were mild to moderate in severity. Positive responses for glycoprotein-specific binding antibodies were induced by 2 weeks in 31 (78%) participants, increased to 34 (85%) participants by 4 weeks, and persisted to 48 weeks in 31 (82%) participants. Most participants developed glycoprotein-specific T-cell responses (20 [59%, 95% CI 41-75] of 34; six participants were removed from the T cell analysis after failing quality control parameters) by 4 weeks after vaccination, and neutralising titres against the cAd3 vector were also increased from baseline (90% inhibitory concentration of 47, 95% CI 30-73) to 4 weeks after vaccination (196, 125-308). INTERPRETATION: The cAd3-EBO S vaccine was safe at both doses, rapidly inducing immune responses in most participants after a single injection. The rapid onset and durability of the vaccine-induced antibodies make this vaccine a strong candidate for emergency deployment in Sudan Ebola virus outbreaks. FUNDING: National Institutes of Health via interagency agreement with Walter Reed Army Institute of Research.

Safety and pharmacokinetics of the Fc-modified HIV-1 human monoclonal antibody VRC01LS: A Phase 1 open-label clinical trial in healthy adults.

BACKGROUND: VRC01 is a human broadly neutralizing monoclonal antibody (bnMAb) against the CD4-binding site of the HIV-1 envelope glycoprotein (Env) that is currently being evaluated in a Phase IIb adult HIV-1 prevention efficacy trial. VRC01LS is a modified version of VRC01, designed for extended serum half-life by increased binding affinity to the neonatal Fc receptor. METHODS AND FINDINGS: This Phase I dose-escalation study of VRC01LS in HIV-negative healthy adults was conducted by the Vaccine Research Center (VRC) at the National Institutes of Health (NIH) Clinical Center (Bethesda, MD). The age range of the study volunteers was 21-50 years; 51% of study volunteers were male and 49% were female. Primary objectives were safety and tolerability of VRC01LS intravenous (IV) infusions at 5, 20, and 40 mg/kg infused once, 20 mg/kg given three times at 12-week intervals, and subcutaneous (SC) delivery at 5 mg/kg delivered once, or three times at 12-week intervals. Secondary objectives were pharmacokinetics (PK), serum neutralization activity, and development of antidrug antibodies. Enrollment began on November 16, 2015, and concluded on August 23, 2017. This report describes the safety data for the first 37 volunteers who received administrations of VRC01LS. There were no serious adverse events (SAEs) or dose-limiting toxicities. Mild malaise and myalgia were the most common adverse events (AEs). There were six AEs assessed as possibly related to VRC01LS administration, and all were mild in severity and resolved during the study. PK data were modeled based on the first dose of VRC01LS in the first 25 volunteers to complete their schedule of evaluations. The mean (±SD) serum concentration 12 weeks after one IV administration of 20 mg/kg or 40 mg/kg were 180 ± 43 µg/mL (n = 7) and 326 ± 35 µg/mL (n = 5), respectively. The mean (±SD) serum concentration 12 weeks after one IV and SC administration of 5 mg/kg were 40 ± 3 µg/mL (n = 2) and 25 ± 5 µg/mL (n = 9), respectively. Over the 5-40 mg/kg IV dose range (n = 16), the clearance was 36 ± 8 mL/d with an elimination half-life of 71 ± 18 days. VRC01LS retained its expected neutralizing activity in serum, and anti-VRC01 antibody responses were not detected. Potential limitations of this study include the small sample size typical of Phase I trials and the need to further describe the PK properties of VRC01LS administered on multiple occasions. CONCLUSIONS: The human bnMAb VRC01LS was safe and well tolerated when delivered intravenously or subcutaneously. The half-life was more than 4-fold greater when compared to wild-type VRC01 historical data. The reduced clearance and extended half-life may make it possible to achieve therapeutic levels with less frequent and lower-dose administrations. This would potentially lower the costs of manufacturing and improve the practicality of using passively administered monoclonal antibodies (mAbs) for the prevention of HIV-1 infection. TRIAL REGISTRATION: ClinicalTrials.gov NCT02599896.

Safety, tolerability, and immunogenicity of two Zika virus DNA vaccine candidates in healthy adults: randomised, open-label, phase 1 clinical trials.

BACKGROUND: The Zika virus epidemic and associated congenital infections have prompted rapid vaccine development. We assessed two new DNA vaccines expressing premembrane and envelope Zika virus structural proteins. METHODS: We did two phase 1, randomised, open-label trials involving healthy adult volunteers. The VRC 319 trial, done in three centres, assessed plasmid VRC5288 (Zika virus and Japanese encephalitis virus chimera), and the VRC 320, done in one centre, assessed plasmid VRC5283 (wild-type Zika virus). Eligible participants were aged 18-35 years in VRC19 and 18-50 years in VRC 320. Participants were randomly assigned 1:1 by a computer-generated randomisation schedule prepared by the study statistician. All participants received intramuscular injection of 4 mg vaccine. In VRC 319 participants were assigned to receive vaccinations via needle and syringe at 0 and 8 weeks, 0 and 12 weeks, 0, 4, and 8 weeks, or 0, 4, and 20 weeks. In VRC 320 participants were assigned to receive vaccinations at 0, 4, and 8 weeks via single-dose needle and syringe injection in one deltoid or split-dose needle and syringe or needle-free injection with the Stratis device (Pharmajet, Golden, CO, USA) in each deltoid. Both trials followed up volunteers for 24 months for the primary endpoint of safety, assessed as local and systemic reactogenicity in the 7 days after each vaccination and all adverse events in the 28 days after each vaccination. The secondary endpoint in both trials was immunogenicity 4 weeks after last vaccination. These trials are registered with ClinicalTrials.gov, numbers NCT02840487 and NCT02996461. FINDINGS: VRC 319 enrolled 80 participants (20 in each group), and VRC 320 enrolled 45 participants (15 in each group). One participant in VRC 319 and two in VRC 320 withdrew after one dose of vaccine, but were included in the safety analyses. Both vaccines were safe and well tolerated. All local and systemic symptoms were mild to moderate. In both studies, pain and tenderness at the injection site was the most frequent local symptoms (37 [46%] of 80 participants in VRC 319 and 36 [80%] of 45 in VRC 320) and malaise and headache were the most frequent systemic symptoms (22 [27%] and 18 [22%], respectively, in VRC 319 and 17 [38%] and 15 [33%], respectively, in VRC 320). For VRC5283, 14 of 14 (100%) participants who received split-dose vaccinations by needle-free injection had detectable positive antibody responses, and the geometric mean titre of 304 was the highest across all groups in both trials. INTERPRETATION: VRC5283 was well tolerated and has advanced to phase 2 efficacy testing. FUNDING: Intramural Research Program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health.

Attenuated PfSPZ Vaccine induces strain-transcending T cells and durable protection against heterologous controlled human malaria infection.

A live-attenuated malaria vaccine, Plasmodium falciparum sporozoite vaccine (PfSPZ Vaccine), confers sterile protection against controlled human malaria infection (CHMI) with Plasmodium falciparum (Pf) parasites homologous to the vaccine strain up to 14 mo after final vaccination. No injectable malaria vaccine has demonstrated long-term protection against CHMI using Pf parasites heterologous to the vaccine strain. Here, we conducted an open-label trial with PfSPZ Vaccine at a dose of 9.0 × 105 PfSPZ administered i.v. three times at 8-wk intervals to 15 malaria-naive adults. After CHMI with homologous Pf parasites 19 wk after final immunization, nine (64%) of 14 (95% CI, 35-87%) vaccinated volunteers remained without parasitemia compared with none of six nonvaccinated controls (P = 0.012). Of the nine nonparasitemic subjects, six underwent repeat CHMI with heterologous Pf7G8 parasites 33 wk after final immunization. Five (83%) of six (95% CI, 36-99%) remained without parasitemia compared with none of six nonvaccinated controls. PfSPZ-specific T-cell and antibody responses were detected in all vaccine recipients. Cytokine production by T cells from vaccinated subjects after in vitro stimulation with homologous (NF54) or heterologous (7G8) PfSPZ were highly correlated. Interestingly, PfSPZ-specific T-cell responses in the blood peaked after the first immunization and were not enhanced by subsequent immunizations. Collectively, these data suggest durable protection against homologous and heterologous Pf parasites can be achieved with PfSPZ Vaccine. Ongoing studies will determine whether protective efficacy can be enhanced by additional alterations in the vaccine dose and number of immunizations.

Protection against malaria at 1 year and immune correlates following PfSPZ vaccination.

An attenuated Plasmodium falciparum (Pf) sporozoite (SPZ) vaccine, PfSPZ Vaccine, is highly protective against controlled human malaria infection (CHMI) 3 weeks after immunization, but the durability of protection is unknown. We assessed how vaccine dosage, regimen, and route of administration affected durable protection in malaria-naive adults. After four intravenous immunizations with 2.7 × 10(5) PfSPZ, 6/11 (55%) vaccinated subjects remained without parasitemia following CHMI 21 weeks after immunization. Five non-parasitemic subjects from this dosage group underwent repeat CHMI at 59 weeks, and none developed parasitemia. Although Pf-specific serum antibody levels correlated with protection up to 21-25 weeks after immunization, antibody levels waned substantially by 59 weeks. Pf-specific T cell responses also declined in blood by 59 weeks. To determine whether T cell responses in blood reflected responses in liver, we vaccinated nonhuman primates with PfSPZ Vaccine. Pf-specific interferon-γ-producing CD8 T cells were present at ∼100-fold higher frequencies in liver than in blood. Our findings suggest that PfSPZ Vaccine conferred durable protection to malaria through long-lived tissue-resident T cells and that administration of higher doses may further enhance protection.

Safety and tolerability of chikungunya virus-like particle vaccine in healthy adults: a phase 1 dose-escalation trial.

BACKGROUND: Chikungunya virus--a mosquito-borne alphavirus--is endemic in Africa and south and southeast Asia and has recently emerged in the Caribbean. No drugs or vaccines are available for treatment or prevention. We aimed to assess the safety, tolerability, and immunogenicity of a new candidate vaccine. METHODS: VRC 311 was a phase 1, dose-escalation, open-label clinical trial of a virus-like particle (VLP) chikungunya virus vaccine, VRC-CHKVLP059-00-VP, in healthy adults aged 18-50 years who were enrolled at the National Institutes of Health Clinical Center (Bethesda, MD, USA). Participants were assigned to sequential dose level groups to receive vaccinations at 10 µg, 20 µg, or 40 µg on weeks 0, 4, and 20, with follow-up for 44 weeks after enrolment. The primary endpoints were safety and tolerability of the vaccine. Secondary endpoints were chikungunya virus-specific immune responses assessed by ELISA and neutralising antibody assays. This trial is registered with ClinicalTrials.gov, NCT01489358. FINDINGS: 25 participants were enrolled from Dec 12, 2011, to March 22, 2012, into the three dosage groups: 10 µg (n=5), 20 µg (n=10), and 40 µg (n=10). The protocol was completed by all five participants at the 10 µg dose, all ten participants at the 20 µg dose, and eight of ten participants at the 40 µg dose; non-completions were for personal circumstances unrelated to adverse events. 73 vaccinations were administered. All injections were well tolerated, with no serious adverse events reported. Neutralising antibodies were detected in all dose groups after the second vaccination (geometric mean titres of the half maximum inhibitory concentration: 2688 in the 10 µg group, 1775 in the 20 µg group, and 7246 in the 40 µg group), and a significant boost occurred after the third vaccination in all dose groups (10 µg group p=0·0197, 20 µg group p<0·0001, and 40 µg group p<0·0001). 4 weeks after the third vaccination, the geometric mean titres of the half maximum inhibitory concentration were 8745 for the 10 µg group, 4525 for the 20 µg group, and 5390 for the 40 µg group. INTERPRETATION: The chikungunya VLP vaccine was immunogenic, safe, and well tolerated. This study represents an important step in vaccine development to combat this rapidly emerging pathogen. Further studies should be done in a larger number of participants and in more diverse populations. FUNDING: Intramural Research Program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases, and National Institutes of Health.

Protection against malaria by intravenous immunization with a nonreplicating sporozoite vaccine.

Consistent, high-level, vaccine-induced protection against human malaria has only been achieved by inoculation of Plasmodium falciparum (Pf) sporozoites (SPZ) by mosquito bites. We report that the PfSPZ Vaccine--composed of attenuated, aseptic, purified, cryopreserved PfSPZ--was safe and well tolerated when administered four to six times intravenously (IV) to 40 adults. Zero of six subjects receiving five doses and three of nine subjects receiving four doses of 1.35 × 10(5) PfSPZ Vaccine and five of six nonvaccinated controls developed malaria after controlled human malaria infection (P = 0.015 in the five-dose group and P = 0.028 for overall, both versus controls). PfSPZ-specific antibody and T cell responses were dose-dependent. These data indicate that there is a dose-dependent immunological threshold for establishing high-level protection against malaria that can be achieved with IV administration of a vaccine that is safe and meets regulatory standards.