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Although several COVID-19 vaccines have been developed so far, they will not be sufficient to meet the global demand. Development of a wider range of vaccines, with different mechanisms of action, could help control the spread of SARS-CoV-2 globally. We developed a protein subunit vaccine against COVID-19 using a dimeric form of the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein as the antigen. We aimed to assess the safety and immunogenicity of this vaccine, ZF2001, and determine the appropriate dose and schedule for an efficacy study. We did two randomised, double-blind, placebo-controlled, phase 1 and phase 2 trials. Phase 1 was done at two university hospitals in Chongqing and Beijing, China, and phase 2 was done at the Hunan Provincial Center for Disease Control and Prevention in Xiangtan, China. Healthy adults aged 18–59 years, without a history of SARS-CoV or SARS-CoV-2 infection, an RT-PCR-positive test result for SARS-CoV-2, a history of contact with confirmed or suspected COVID-19 cases, and severe allergies to any component of the vaccine were eligible for enrolment. In phase 1, participants were randomly assigned (2:2:1) to receive three doses of the vaccine (25 μg or 50 μg) or placebo intramuscularly, 30 days apart. In phase 2, participants were randomly assigned (1:1:1:1:1:1) to receive the vaccine (25 μg or 50 μg) or placebo intramuscularly, 30 days apart, in either a two-dose schedule or a three-dose schedule. Investigators, participants, and the laboratory team were masked to group allocation. For phase 1, the primary outcome was safety, measured by the occurrence of adverse events and serious adverse events. For phase 2, the primary outcome was safety and immunogenicity (the seroconversion rate and the magnitude, in geometric mean titres [GMTs], of SARS-CoV-2-neutralising antibodies). Analyses were done on an intention-to-treat and per-protocol basis. These trials are registered with ClinicalTrials.gov (NCT04445194 and NCT04466085) and participant follow-up is ongoing. Between June 22 and July 3, 2020, 50 participants were enrolled into the phase 1 trial and randomly assigned to receive three doses of placebo (n=10), the 25 μg vaccine (n=20), or the 50 μg vaccine (n=20). The mean age of participants was 32·6 (SD 9·4) years. Between July 12 and July 17, 2020, 900 participants were enrolled into the phase 2 trial and randomly assigned to receive two doses of placebo (n=150), 25 μg vaccine (n=150), or 50 μg vaccine (n=150), or three doses of placebo (n=150), 25 μg vaccine (n=150), or 50 μg vaccine (n=150). The mean age of participants was 43·5 (SD 9·2) years. In both phase 1 and phase 2, adverse events reported within 30 days after vaccination were mild or moderate (grade 1 or 2) in most cases (phase 1: six [60%] of ten participants in the placebo group, 14 [70%] of 20 in the 25 μg group, and 18 [90%] of 20 in the 50 μg group; phase 2: 37 [25%] of 150 in the two-dose placebo group, 43 [29%] of 150 in the two-dose 25 μg group, 50 [33%] of 150 in the two-dose 50 μg group, 47 [31%] of 150 in the three-dose placebo group, 72 [48%] of 150 in the three-dose 25 μg group, and 65 [43%] of 150 in the three-dose 50 μg group). In phase 1, two (10%) grade 3 or worse adverse events were reported in the 50 μg group. In phase 2, grade 3 or worse adverse events were reported by 18 participants (four [3%] in the two-dose 25 μg vaccine group, two [1%] in the two-dose 50 μg vaccine group, two [1%] in the three-dose placebo group, four [3%] in the three-dose 25 μg vaccine group, and six [4%] in the three-dose 50 μg vaccine group), and 11 were considered vaccine related (two [1%] in the two-dose 25 μg vaccine group, one [1%] in the two-dose 50 μg vaccine group, one [1%] in the three-dose placebo group, two [1%] in the three-dose 25 μg vaccine group, and five [3%] in the three-dose 50 μg vaccine group); seven participants reported serious adverse events (one [1%] in the two-dose 25 μg vaccine group, one [1%] in the two-dose 50 μg vaccine group, two [1%] in the three-dose placebo group, one [1%] in the three-dose 25 μg vaccine group, and two [1%] in the three-dose 50 μg vaccine group), but none was considered vaccine related. In phase 2, on the two-dose schedule, seroconversion rates of neutralising antibodies 14 days after the second dose were 76% (114 of 150 participants) in the 25 μg group and 72% (108 of 150) in the 50 μg group; on the three-dose schedule, seroconversion rates of neutralising antibodies 14 days after the third dose were 97% (143 of 148 participants) in the 25 μg group and 93% (138 of 148) in the 50 μg group. In the two-dose groups in phase 2, the SARS-CoV-2-neutralising GMTs 14 days after the second dose were 17·7 (95% CI 13·6–23·1) in the 25 μg group and 14·1 (10·8–18·3) in the 50 μg group. In the three-dose groups in phase 2, the SARS-CoV-2-neutralising GMTs 14 days after the third dose were 102·5 (95% CI 81·8–128·5) in the 25 μg group and 69·1 (53·0–90·0) in the 50 μg group. The protein subunit vaccine ZF2001 appears to be well tolerated and immunogenic. The safety and immunogenicity data from the phase 1 and 2 trials support the use of the 25 μg dose in a three-dose schedule in an ongoing phase 3 trial for large-scale evaluation of ZF2001's safety and efficacy. National Program on Key Research Project of China, National Science and Technology Major Projects of Drug Discovery, Strategic Priority Research Program of the Chinese Academy of Sciences, and Anhui Zhifei Longcom Biopharmaceutical. For the Chinese translation of the abstract see Supplementary Materials section.

In this trial of a recombinant VZV glycoprotein E subunit vaccine with the adjuvant AS01 B , the risk of herpes zoster and postherpetic neuralgia is shown to be significantly lower in association with the vaccine than with placebo among persons 70 years of age or older. Herpes zoster, or shingles, results from the reactivation of latent varicella–zoster virus (VZV) and typically manifests as a vesicular, painful dermatomal rash. 1 , 2 The most common complication of herpes zoster, postherpetic neuralgia, manifests as chronic neuropathic pain that can greatly limit daily activities. 1 , 3 – 6 The overall incidence of herpes zoster is 2.0 to 4.6 cases per 1000 person-years but increases with age to 10.0 to 12.8 per 1000 person-years among persons 80 years of age or older. 7 – 10 Similarly, the incidence of postherpetic neuralgia also increases with age. 10 – 13 Antiviral therapy can reduce the duration of herpes zoster rash . . .

•CMV seronegative girls between 12 and 17 years of age received CMV glycoprotein B (gB) vaccine with MF59 or saline placebo at 0, 1 and 6 months.•The vaccine was generally well tolerated, although local and systemic adverse events were significantly more common in the vaccine group.•In the per protocol population vaccine efficacy was 43% after 3 doses, p=0.20 and 45%, p=0.08 after 2 doses.•We conclude the vaccine was safe and immunogenic and although the efficacy did not reach significance, the results are consistent with a previous study in adult women (Pass et al NEJM 360:1191, 2009) using the same formulation. Cytomegalovirus (CMV) is a leading cause of congenital infection and an important target for vaccine development. CMV seronegative girls between 12 and 17 years of age received CMV glycoprotein B (gB) vaccine with MF59 or saline placebo at 0, 1 and 6 months. Blood and urine were collected throughout the study for evidence of CMV infection based on PCR and/or seroconversion to non-vaccine CMV antigens. 402 CMV seronegative subjects were vaccinated (195 vaccine, 207 placebo). The vaccine was generally well tolerated, although local and systemic adverse events were significantly more common in the vaccine group. The vaccine induced gB antibody in all vaccine recipients with a gB geometric mean titer of 13,400EU; 95%CI 11,436, 15,700, after 3 doses. Overall, 48 CMV infections were detected (21 vaccine, 27 placebo). In the per protocol population (124 vaccine, 125 placebo) vaccine efficacy was 43%; 95%CI: −36; 76, p=0.20. The most significant difference was after 2 doses, administered as per protocol; vaccine efficacy 45%, 95%CI: −9; 72, p=0.08. The vaccine was safe and immunogenic. Although the efficacy did not reach conventional levels of significance, the results are consistent with a previous study in adult women (Pass et al. N Engl J Med 2009;360:1191) using the same formulation.

Adjuvant-containing subunit vaccines represent a promising approach for protection against tuberculosis (TB), but current candidates require refrigerated storage. Here we present results from a randomized, double-blinded Phase 1 clinical trial (NCT03722472) evaluating the safety, tolerability, and immunogenicity of a thermostable lyophilized single-vial presentation of the ID93 + GLA-SE vaccine candidate compared to the non-thermostable two-vial vaccine presentation in healthy adults. Participants were monitored for primary, secondary, and exploratory endpoints following intramuscular administration of two vaccine doses 56 days apart. Primary endpoints included local and systemic reactogenicity and adverse events. Secondary endpoints included antigen-specific antibody (IgG) and cellular immune responses (cytokine-producing peripheral blood mononuclear cells and T cells). Both vaccine presentations are safe and well tolerated and elicit robust antigen-specific serum antibody and Th1-type cellular immune responses. Compared to the non-thermostable presentation, the thermostable vaccine formulation generates greater serum antibody responses ( p  < 0.05) and more antibody-secreting cells ( p  < 0.05). In this work, we show the thermostable ID93 + GLA-SE vaccine candidate is safe and immunogenic in healthy adults. Here the authors present results from a randomized, double-blinded Phase 1 clinical trial, testing a thermostable presentation of a clinical-stage adjuvanted subunit tuberculosis vaccine candidate. The vaccine candidate is safe and well tolerated, and elicits comparable or improved immune responses compared to the non-thermostable presentation.

As part of the accelerated development of vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), we report a dose-finding and adjuvant justification study of SCB-2019, a protein subunit vaccine candidate containing a stabilised trimeric form of the spike (S)-protein (S-Trimer) combined with two different adjuvants. Our study is a phase 1, randomised, double-blind placebo-controlled trial at a specialised clinical trials centre in Australia. We enrolled healthy adult volunteers in two age groups: younger adults (aged 18–54 years) and older adults (aged 55–75 years). Participants were randomly allocated either vaccine or placebo using a list prepared by the study funder. Participants were to receive two doses of SCB-2019 (either 3 μg, 9 μg, or 30 μg) or a placebo (0·9% NaCl) 21 days apart. SCB-2019 either had no adjuvant (S-Trimer protein alone) or was adjuvanted with AS03 or CpG/Alum. The assigned treatment was administered in opaque syringes to maintain masking of assignments. Reactogenicity was assessed for 7 days after each vaccination. Humoral responses were measured as SCB-2019 binding IgG antibodies and ACE2-competitive blocking IgG antibodies by ELISA and as neutralising antibodies by wild-type SARS-CoV-2 microneutralisation assay. Cellular responses to pooled S-protein peptides were measured by flow-cytometric intracellular cytokine staining. This trial is registered with ClinicalTrials.gov, NCT04405908; this is an interim analysis and the study is continuing. Between June 19 and Sept 23, 2020, 151 volunteers were enrolled; three people withdrew, two for personal reasons and one with an unrelated serious adverse event (pituitary adenoma). 148 participants had at least 4 weeks of follow-up after dose two and were included in this analysis (database lock, Oct 23, 2020). Vaccination was well tolerated, with two grade 3 solicited adverse events (pain in 9 μg AS03-adjuvanted and 9 μg CpG/Alum-adjuvanted groups). Most local adverse events were mild injection-site pain, and local events were more frequent with SCB-2019 formulations containing AS03 adjuvant (44–69%) than with those containing CpG/Alum adjuvant (6–44%) or no adjuvant (3–13%). Systemic adverse events were more frequent in younger adults (38%) than in older adults (17%) after the first dose but increased to similar levels in both age groups after the second dose (30% in older and 34% in younger adults). SCB-2019 with no adjuvant elicited minimal immune responses (three seroconversions by day 50), but SCB-2019 with fixed doses of either AS03 or CpG/Alum adjuvants induced high titres and seroconversion rates of binding and neutralising antibodies in both younger and older adults (anti-SCB-2019 IgG antibody geometric mean titres at day 36 were 1567–4452 with AS03 and 174–2440 with CpG/Alum). Titres in all AS03 dose groups and the CpG/Alum 30 μg group were higher than were those recorded in a panel of convalescent serum samples from patients with COVID-19. Both adjuvanted SCB-2019 formulations elicited T-helper-1-biased CD4+ T-cell responses. The SCB-2019 vaccine, comprising S-Trimer protein formulated with either AS03 or CpG/Alum adjuvants, elicited robust humoral and cellular immune responses against SARS-CoV-2, with high viral neutralising activity. Both adjuvanted vaccine formulations were well tolerated and are suitable for further clinical development. Clover Biopharmaceuticals and the Coalition for Epidemic Preparedness Innovations.

In this randomized, controlled trial involving more than 15,000 participants 50 years of age or older, a varicella–zoster virus subunit vaccine with AS01B adjuvant was found to have an efficacy of more than 96% in preventing herpes zoster. Herpes zoster, or shingles, results from the reactivation of latent varicella–zoster virus (VZV) in the dorsal-root or cranial-nerve ganglia, usually decades after primary infection. 1 , 2 Herpes zoster is characterized by a vesicular rash with a unilateral and dermatomal distribution and is almost always accompanied by pain. More than 90% of adults have been infected with VZV and are at risk for herpes zoster. 3 , 4 Although herpes zoster is most frequent in adults who are 50 years of age or older owing to immunosenescence, it can occur at any age, especially when cell-mediated immunity is decreased as a result of disease . . .

Efficacy of live oral rotavirus vaccines is reduced in low-income compared with high-income settings. Parenteral non-replicating rotavirus vaccines might offer benefits over oral vaccines. We assessed the safety and immunogenicity of the P2-VP8-P[8] subunit rotavirus vaccine at different doses in South African toddlers and infants. This double-blind, randomised, placebo-controlled, dose-escalation trial was done at a single research unit based at a hospital in South Africa in healthy HIV-uninfected toddlers (aged 2 to <3 years) and term infants (aged 6 to <8 weeks, without previous rotavirus vaccination). Block randomisation (computer-generated, electronic allocation) was used to assign eligible toddlers (in a 6:1 ratio) and infants (in a 3:1 ratio) in each dose cohort (10 μg, followed by 30 μg, then 60 μg if doses tolerated) to parenteral P2-VP8-P[8] subunit rotavirus or placebo injection. The two highest tolerated doses were then assessed in an expanded cohort (in a 1:1:1 ratio). Parents of participants and clinical, data, and laboratory staff were masked to treatment assignment. P2-VP8-P[8] vaccine versus placebo was assessed first in toddlers (single injection) and then in infants (three injections 4 weeks apart). The primary safety endpoints were local and systemic reactions within 7 days after each injection, adverse events within 28 days after each injection, and all serious adverse events, assessed in toddlers and infants who received at least one dose. In infants receiving all study injections, primary immunogenicity endpoints were anti-P2-VP8-P[8] IgA and IgG and neutralising antibody seroresponses and geometric mean titres 4 weeks after the third injection. This trial is registered at ClinicalTrials.gov, number NCT02109484. Between March 17, 2014, and Sept 29, 2014, 42 toddlers (36 to vaccine and six to placebo) and 48 infants (36 to vaccine and 12 to placebo) were enrolled in the dose-escalation phase, in which the 30 μg and 60 μg doses where found to be the highest tolerated doses. A further 114 infants were enrolled in the expanded cohort between Nov 3, 2014, and March 20, 2015, and all 162 infants (12 assigned to 10 μg, 50 to 30 μg, 50 to 60 μg, and 50 to placebo) were included in the safety analysis. Serum IgA seroresponses were observed in 38 (81%, 95% CI 67–91) of 47 infants in the 30 μg group and 32 (68%, 53–81) of 47 in the 60 μg group, compared with nine (20%, 10–35) of 45 in the placebo group; adjusted IgG seroresponses were seen in 46 (98%, 89–100) of 47 infants in the 30 μg group and 47 (100%; 92–100) of 47 in the 60 μg group, compared with four (9%, 2·5–21) of 45 in the placebo group; and adjusted neutralising antibody seroresponses against the homologous Wa-strain were seen in 40 (85%, 72–94) of 47 infants in both the 30 μg and 60 μg groups, compared with three (7%, 1·4–18) of 45 participants in the placebo group. Solicited reactions following any injection occurred with similar frequency and severity in participants receiving vaccine and those receiving placebo. Unsolicited adverse events were mostly mild and occurred at a similar frequency between groups. Eight serious adverse events (one with placebo, two with 30 μg, and five with 60 μg) occurred in seven infants within 28 days of any study injection, none of which were deemed related to study treatment. The parenteral P2-VP8-P[8] vaccine was well tolerated and immunogenic in infants, providing a novel approach to vaccination against rotavirus disease. On the basis of these results, a phase 1/2 trial of a trivalent P2-VP8 (P[4], P[6], and P[8]) subunit vaccine is underway at three sites in South Africa. Bill & Melinda Gates Foundation.

When the adjuvanted HZ subunit vaccine candidate was coadministered with a quadrivalent seasonal influenza vaccine, no interference in the immune responses were observed, and no safety concerns were identified. Abstract Background The immunogenicity and safety of an adjuvanted herpes zoster subunit (HZ/su) vaccine when coadministered with a quadrivalent seasonal inactivated influenza vaccine (IIV4) was investigated in a phase 3, open-label, randomized clinical trial in adults aged ≥50 years. Methods Subjects were randomized 1:1 to receive either HZ/su (varicella zoster virus glycoprotein E; AS01B Adjuvant System) and IIV4 at day 0 followed by a second HZ/su dose at month 2 (coadministration group), or IIV4 at month 0 and HZ/su at months 2 and 4 (control group). The primary objectives were the HZ/su vaccine response rate in the coadministration group and the noninferiority of the antibody responses to HZ/su and IIV4 in the coadministration compared with the control group. Safety information was collected throughout the duration of the study. Results A total of 413 subjects were vaccinated in the coadministration group and 415 in the control group. The HZ/su vaccine response rate in the coadministration group was 95.8% (95% confidence interval, 93.3%–97.6%) and the anti–glycoprotein E GMCControl/Coadmin ratio was 1.08 (.97–1.20). The primary noninferiority objectives were met. No safety concerns were observed. Conclusions No interference in the immune responses to either vaccine was observed when the vaccines were coadministered, and no safety concerns were identified. Clinical Trials Registration NCT01954251.

While live oral rotavirus vaccines (LORVs) are effective at preventing severe rotavirus gastroenteritis (SRVGE), they perform sub-optimally in the settings with the highest burden. Parenteral rotavirus vaccines could have greater efficacy by bypassing the gut, where interference with LORVs may occur. A novel parenteral rotavirus subunit vaccine (TV P2-VP8) was evaluated in a Phase 3 study for safety, immunogenicity, and relative efficacy in healthy African infants. Participating infants were randomized at 6–8 weeks of age to receive either three doses of TV P2-VP8 intramuscularly (IM) plus oral placebo or two doses of ROTARIX® (oral) plus IM placebo. The trial was designed to enroll a total of 8200 participants in two stages separated by an interim analysis conducted upon accrual of a predetermined number of SRVGE cases. Data at interim analysis indicated a low probability of demonstrating TV P2-VP8 superiority compared to ROTARIX in prevention of SRVGE, and the study was closed early. 4055 infants were enrolled and provided safety data. TV P2-VP8 was safe and well tolerated, with no safety concerns indicated. Virus neutralizing and IgG binding antibody seroresponses to TV-P2-VP8 were detected in most participants. The crude attack rates of SRVGE in the per-protocol population (n = 3477) were 4.51 % (TV P2-VP8) and 2.57 % (ROTARIX). The relative vaccine efficacy (RVE) against SRVGE for TV P2-VP8 was −77.68 % (95 % CI, −162.38, −21.54). The RVE against SRVGE in the first and second year of life was −91.67 % (95 % CI, −199.20, −24.35) and − 31.97 % (95 % CI, −220.37, 44.49), respectively. The RVE against rotavirus gastroenteritis of any severity was −47.78 % (95 % CI, −89.63, −15.59). TV P2-VP8 provided inferior protection against SRVGE compared to ROTARIX. The vaccine candidate was safe, immunogenic, and well-tolerated by infants. Continued efforts are needed to identify alternative rotavirus vaccines with improved efficacy in LMICs. Trial Registration:NCT04010448; PACTR201907491834482. •The TV P2-VP8 vaccine candidate was safe and immunogenic.•Three doses of TV P2-VP8 were inferior to two doses of ROTARIX® in preventing severe rotavirus gastroenteritis.•Study provides insight to guide future development of rotavirus vaccine candidates.

Influenza poses a significant global healthcare burden, with up to 1 billion infections annually, and poorer outcomes in vulnerable populations such as older adults. Vaccination effectiveness is often lower in elderly individuals. By adding an adjuvant and using cell-based vaccine production methods, the MF59-adjuvanted quadrivalent cell-based influenza vaccine (aQIVc) may boost immunogenicity and vaccine effectiveness in this population. We report the results of a randomised proof-of-concept study, investigating the immunogenicity and safety of aQIVc. Eligible participants aged ≥50 years were randomised 1: 1:1:1 to receive aQIVc (n = 116), a non-adjuvanted quadrivalent cell-based influenza vaccine (QIVc; n = 119), an MF59-adjuvanted quadrivalent egg-based influenza vaccine (aQIV; n = 116), or a high-dose quadrivalent recombinant influenza vaccine (QIVr; n = 120). The primary objective was to assess immunogenicity of aQIVc vs the comparators by haemagglutination inhibition (HI) assay 28 days post-vaccination. Secondary objectives included immunogenicity of aQIVc vs comparators 28 days and 180 post-vaccination by microneutralisation assay and 180 days post-vaccination by HI assay; and reactogenicity and safety of all study vaccines. Compared with QIVc and aQIV, aQIVc elicited a higher immune response (adjusted geometric mean titre [GMT] ratio range 1.18–1.85) against all four influenza strains at Day 29. Against QIVr, aQIVc elicited lower responses against A strains (adjusted GMT ratio range 0.79–0.84), and higher responses against B strains (adjusted GMT ratio range 1.15–1.26). Estimated GMT ratios were generally higher in the subgroup of participants aged ≥65 years vs those aged 50–64 years. aQIVc was well tolerated, eliciting similar rates of solicited local adverse events (AE) and slightly higher rates of solicited systemic AE than aQIV, and a higher rate of all solicited AE than QIVc and QIVr. No safety concern was identified. These data support further investigation of additional formulations of aQIVc in adults aged ≥50 years. Clinical trial registry:NCT04576702 •We assessed an adjuvanted, cell-based influenza vaccine (aQIVc) in adults ≥50 years•aQIVc elicited higher immune responses than a non-adjuvanted comparator•aQIVc elicited higher immune responses than an egg-based adjuvanted comparator•aQIVc showed an acceptable safety profile; no safety concerns were identified•These data are proof-of-concept for seasonal aQIVc vaccination in adults ≥50 years