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A vaccine to protect against COVID-19 is urgently needed. We aimed to assess the safety, tolerability, and immunogenicity of a recombinant adenovirus type-5 (Ad5) vectored COVID-19 vaccine expressing the spike glycoprotein of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) strain. We did a dose-escalation, single-centre, open-label, non-randomised, phase 1 trial of an Ad5 vectored COVID-19 vaccine in Wuhan, China. Healthy adults aged between 18 and 60 years were sequentially enrolled and allocated to one of three dose groups (5 × 1010, 1 × 1011, and 1·5 × 1011 viral particles) to receive an intramuscular injection of vaccine. The primary outcome was adverse events in the 7 days post-vaccination. Safety was assessed over 28 days post-vaccination. Specific antibodies were measured with ELISA, and the neutralising antibody responses induced by vaccination were detected with SARS-CoV-2 virus neutralisation and pseudovirus neutralisation tests. T-cell responses were assessed by enzyme-linked immunospot and flow-cytometry assays. This study is registered with ClinicalTrials.gov, NCT04313127. Between March 16 and March 27, 2020, we screened 195 individuals for eligibility. Of them, 108 participants (51% male, 49% female; mean age 36·3 years) were recruited and received the low dose (n=36), middle dose (n=36), or high dose (n=36) of the vaccine. All enrolled participants were included in the analysis. At least one adverse reaction within the first 7 days after the vaccination was reported in 30 (83%) participants in the low dose group, 30 (83%) participants in the middle dose group, and 27 (75%) participants in the high dose group. The most common injection site adverse reaction was pain, which was reported in 58 (54%) vaccine recipients, and the most commonly reported systematic adverse reactions were fever (50 [46%]), fatigue (47 [44%]), headache (42 [39%]), and muscle pain (18 [17%]. Most adverse reactions that were reported in all dose groups were mild or moderate in severity. No serious adverse event was noted within 28 days post-vaccination. ELISA antibodies and neutralising antibodies increased significantly at day 14, and peaked 28 days post-vaccination. Specific T-cell response peaked at day 14 post-vaccination. The Ad5 vectored COVID-19 vaccine is tolerable and immunogenic at 28 days post-vaccination. Humoral responses against SARS-CoV-2 peaked at day 28 post-vaccination in healthy adults, and rapid specific T-cell responses were noted from day 14 post-vaccination. Our findings suggest that the Ad5 vectored COVID-19 vaccine warrants further investigation. National Key R&D Program of China, National Science and Technology Major Project, and CanSino Biologics.

In March 2020, the World Health Organization (WHO) declared coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 1 , a pandemic. With rapidly accumulating numbers of cases and deaths reported globally 2 , a vaccine is urgently needed. Here we report the available safety, tolerability and immunogenicity data from an ongoing placebo-controlled, observer-blinded dose-escalation study (ClinicalTrials.gov identifier NCT04368728) among 45 healthy adults (18–55 years of age), who were randomized to receive 2 doses—separated by 21 days—of 10 μg, 30 μg or 100 μg of BNT162b1. BNT162b1 is a lipid-nanoparticle-formulated, nucleoside-modified mRNA vaccine that encodes the trimerized receptor-binding domain (RBD) of the spike glycoprotein of SARS-CoV-2. Local reactions and systemic events were dose-dependent, generally mild to moderate, and transient. A second vaccination with 100 μg was not administered because of the increased reactogenicity and a lack of meaningfully increased immunogenicity after a single dose compared with the 30-μg dose. RBD-binding IgG concentrations and SARS-CoV-2 neutralizing titres in sera increased with dose level and after a second dose. Geometric mean neutralizing titres reached 1.9–4.6-fold that of a panel of COVID-19 convalescent human sera, which were obtained at least 14 days after a positive SARS-CoV-2 PCR. These results support further evaluation of this mRNA vaccine candidate. In a dose-escalation study of the COVID-19 RNA vaccine BNT162b1 in 45 healthy adults, RBD-binding IgG concentrations and SARS-CoV-2 neutralizing titres in sera increased with dose level and after a second vaccine dose.

The pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) might be curtailed by vaccination. We assessed the safety, reactogenicity, and immunogenicity of a viral vectored coronavirus vaccine that expresses the spike protein of SARS-CoV-2. We did a phase 1/2, single-blind, randomised controlled trial in five trial sites in the UK of a chimpanzee adenovirus-vectored vaccine (ChAdOx1 nCoV-19) expressing the SARS-CoV-2 spike protein compared with a meningococcal conjugate vaccine (MenACWY) as control. Healthy adults aged 18–55 years with no history of laboratory confirmed SARS-CoV-2 infection or of COVID-19-like symptoms were randomly assigned (1:1) to receive ChAdOx1 nCoV-19 at a dose of 5 × 1010 viral particles or MenACWY as a single intramuscular injection. A protocol amendment in two of the five sites allowed prophylactic paracetamol to be administered before vaccination. Ten participants assigned to a non-randomised, unblinded ChAdOx1 nCoV-19 prime-boost group received a two-dose schedule, with the booster vaccine administered 28 days after the first dose. Humoral responses at baseline and following vaccination were assessed using a standardised total IgG ELISA against trimeric SARS-CoV-2 spike protein, a muliplexed immunoassay, three live SARS-CoV-2 neutralisation assays (a 50% plaque reduction neutralisation assay [PRNT50]; a microneutralisation assay [MNA50, MNA80, and MNA90]; and Marburg VN), and a pseudovirus neutralisation assay. Cellular responses were assessed using an ex-vivo interferon-γ enzyme-linked immunospot assay. The co-primary outcomes are to assess efficacy, as measured by cases of symptomatic virologically confirmed COVID-19, and safety, as measured by the occurrence of serious adverse events. Analyses were done by group allocation in participants who received the vaccine. Safety was assessed over 28 days after vaccination. Here, we report the preliminary findings on safety, reactogenicity, and cellular and humoral immune responses. The study is ongoing, and was registered at ISRCTN, 15281137, and ClinicalTrials.gov, NCT04324606. Between April 23 and May 21, 2020, 1077 participants were enrolled and assigned to receive either ChAdOx1 nCoV-19 (n=543) or MenACWY (n=534), ten of whom were enrolled in the non-randomised ChAdOx1 nCoV-19 prime-boost group. Local and systemic reactions were more common in the ChAdOx1 nCoV-19 group and many were reduced by use of prophylactic paracetamol, including pain, feeling feverish, chills, muscle ache, headache, and malaise (all p<0·05). There were no serious adverse events related to ChAdOx1 nCoV-19. In the ChAdOx1 nCoV-19 group, spike-specific T-cell responses peaked on day 14 (median 856 spot-forming cells per million peripheral blood mononuclear cells, IQR 493–1802; n=43). Anti-spike IgG responses rose by day 28 (median 157 ELISA units [EU], 96–317; n=127), and were boosted following a second dose (639 EU, 360–792; n=10). Neutralising antibody responses against SARS-CoV-2 were detected in 32 (91%) of 35 participants after a single dose when measured in MNA80 and in 35 (100%) participants when measured in PRNT50. After a booster dose, all participants had neutralising activity (nine of nine in MNA80 at day 42 and ten of ten in Marburg VN on day 56). Neutralising antibody responses correlated strongly with antibody levels measured by ELISA (R2=0·67 by Marburg VN; p<0·001). ChAdOx1 nCoV-19 showed an acceptable safety profile, and homologous boosting increased antibody responses. These results, together with the induction of both humoral and cellular immune responses, support large-scale evaluation of this candidate vaccine in an ongoing phase 3 programme. UK Research and Innovation, Coalition for Epidemic Preparedness Innovations, National Institute for Health Research (NIHR), NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and the German Center for Infection Research (DZIF), Partner site Gießen-Marburg-Langen.

This is the first randomised controlled trial for assessment of the immunogenicity and safety of a candidate non-replicating adenovirus type-5 (Ad5)-vectored COVID-19 vaccine, aiming to determine an appropriate dose of the candidate vaccine for an efficacy study. This randomised, double-blind, placebo-controlled, phase 2 trial of the Ad5-vectored COVID-19 vaccine was done in a single centre in Wuhan, China. Healthy adults aged 18 years or older, who were HIV-negative and previous severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection-free, were eligible to participate and were randomly assigned to receive the vaccine at a dose of 1 × 1011 viral particles per mL or 5 × 1010 viral particles per mL, or placebo. Investigators allocated participants at a ratio of 2:1:1 to receive a single injection intramuscularly in the arm. The randomisation list (block size 4) was generated by an independent statistician. Participants, investigators, and staff undertaking laboratory analyses were masked to group allocation. The primary endpoints for immunogenicity were the geometric mean titres (GMTs) of specific ELISA antibody responses to the receptor binding domain (RBD) and neutralising antibody responses at day 28. The primary endpoint for safety evaluation was the incidence of adverse reactions within 14 days. All recruited participants who received at least one dose were included in the primary and safety analyses. This study is registered with ClinicalTrials.gov, NCT04341389. 603 volunteers were recruited and screened for eligibility between April 11 and 16, 2020. 508 eligible participants (50% male; mean age 39·7 years, SD 12·5) consented to participate in the trial and were randomly assigned to receive the vaccine (1 × 1011 viral particles n=253; 5 × 1010 viral particles n=129) or placebo (n=126). In the 1 × 1011 and 5 × 1010 viral particles dose groups, the RBD-specific ELISA antibodies peaked at 656·5 (95% CI 575·2–749·2) and 571·0 (467·6–697·3), with seroconversion rates at 96% (95% CI 93–98) and 97% (92–99), respectively, at day 28. Both doses of the vaccine induced significant neutralising antibody responses to live SARS-CoV-2, with GMTs of 19·5 (95% CI 16·8–22·7) and 18·3 (14·4–23·3) in participants receiving 1 × 1011 and 5 × 1010 viral particles, respectively. Specific interferon γ enzyme-linked immunospot assay responses post vaccination were observed in 227 (90%, 95% CI 85–93) of 253 and 113 (88%, 81–92) of 129 participants in the 1 × 1011 and 5 × 1010 viral particles dose groups, respectively. Solicited adverse reactions were reported by 183 (72%) of 253 and 96 (74%) of 129 participants in the 1 × 1011 and 5 × 1010 viral particles dose groups, respectively. Severe adverse reactions were reported by 24 (9%) participants in the 1 × 1011 viral particles dose group and one (1%) participant in the 5 × 1010 viral particles dose group. No serious adverse reactions were documented. The Ad5-vectored COVID-19 vaccine at 5 × 1010 viral particles is safe, and induced significant immune responses in the majority of recipients after a single immunisation. National Key R&D Programme of China, National Science and Technology Major Project, and CanSino Biologics.

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. 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. 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. VRC5283 was well tolerated and has advanced to phase 2 efficacy testing. Intramural Research Program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health.

Two inoculations with a new SARS-CoV-2 mRNA-based vaccine that encodes a protein in the coronavirus spike elicited high titers of virus-neutralizing antibody in healthy adult volunteers. Virus-specific T-cell responses were also elicited. Interim findings indicated that a dose of 100 μg per injection maximized immune response and minimized the reactogenicity of the vaccine.

Chikungunya disease is a growing global public health concern. Vimkunya (previously chikungunya virus virus-like particle vaccine, previously PXVX0317) is a single-dose, pre-filled syringe for intramuscular injection. Here, we report safety, tolerability, and immunogenicity data for Vimkunya versus placebo in healthy adolescents and adults aged 12–64 years, and evaluate lot-to-lot consistency. This pivotal phase 3, randomised, double-blind, placebo-controlled, parallel-group trial was done at 47 clinical trial sites in the USA. Eligible participants were healthy adolescents and adults aged 12–64 years. Participants were divided into three age strata (12–17 years, 18–45 years, and 46–64 years) within each site and randomly assigned (2:2:2:1) to receive one of three consecutively manufactured lots of Vimkunya or placebo (same excipient composition without chikungunya virus virus-like particle or aluminium hydroxide components) on study day 1. Neither participants, nor clinical site personnel, nor the funder knew participants' individual treatment assignments until all participants completed their involvement in the trial and the database was cleaned and locked. Participants attended a screening visit, followed by a day 1 visit that included random assignment, blood sample collection, and administration of a single dose of Vimkunya or placebo by intramuscular injection in the deltoid muscle. The coprimary endpoints were: the difference in chikungunya virus serum neutralising antibody seroreponse rate (vaccine minus placebo) at day 22; chikungunya virus serum neutralising antibody geometric mean titre (GMT) at day 22 for vaccine and placebo; and chikungunya virus serum neutralising GMT ratio at day 22 between all three pairs of vaccine lots (A:B, B:C, and A:C) in adults aged 18–45 years. The trial is registered with ClinicalTrials.gov, NCT05072080 and EudraCT, 2023-001124-42. Between Sept 29, 2021, and Sept 23, 2022, 4215 participants were screened, of whom 3258 were eligible and enrolled (1667 [51·2%] female and 1591 [48·8%] male), and 3254 (99·9%) received either Vimkunya (n=2790) or placebo (n=464). The immunogenicity evaluable population included 2983 participants, of whom 2559 received Vimkunya and 424 received placebo. At day 22, 2503 (97·8%) of 2559 participants in the Vimkunya group had a seroresponse, compared with five (1·2%) of 424 participants in the placebo group for the immunogenicity evaluable population. The seroreponse rate difference was 96·6% (95% CI 95·0–97·5; p<0·0001). In the immunogenicity evaluable population, chikungunya virus serum neutralising antibody GMT at day 22 for the vaccine group was 1618 and for the placebo group was 7·9 (p<0·0001). At day 22, the serum neutralising GMT ratios for the pairs of lots (A:B, B:C, and A:C) were 0·98 (95% CI 0·85–1·14), 0·97 (0·84–1·12), and 0·95 (0·82–1·10), respectively. Vimkunya had a favourable safety profile; most adverse events were self-limiting and grade 1 or 2 in severity. The most common adverse events were injection site pain (656 [23·7%] of 2764 participants in the vaccine group), fatigue (551 [19·9%] of 2764), headache (498 [18·0%] of 2765), and myalgia (486 [17·6%] of 2764). Vimkunya induces a rapid and robust immune response. These findings support the potential for this vaccine to protect individuals aged 12–64 years from disease caused by chikungunya virus. Emergent BioSolutions and Bavarian Nordic.

We developed a heterologous COVID-19 vaccine consisting of two components, a recombinant adenovirus type 26 (rAd26) vector and a recombinant adenovirus type 5 (rAd5) vector, both carrying the gene for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike glycoprotein (rAd26-S and rAd5-S). We aimed to assess the safety and immunogenicity of two formulations (frozen and lyophilised) of this vaccine. We did two open, non-randomised phase 1/2 studies at two hospitals in Russia. We enrolled healthy adult volunteers (men and women) aged 18–60 years to both studies. In phase 1 of each study, we administered intramuscularly on day 0 either one dose of rAd26-S or one dose of rAd5-S and assessed the safety of the two components for 28 days. In phase 2 of the study, which began no earlier than 5 days after phase 1 vaccination, we administered intramuscularly a prime-boost vaccination, with rAd26-S given on day 0 and rAd5-S on day 21. Primary outcome measures were antigen-specific humoral immunity (SARS-CoV-2-specific antibodies measured by ELISA on days 0, 14, 21, 28, and 42) and safety (number of participants with adverse events monitored throughout the study). Secondary outcome measures were antigen-specific cellular immunity (T-cell responses and interferon-γ concentration) and change in neutralising antibodies (detected with a SARS-CoV-2 neutralisation assay). These trials are registered with ClinicalTrials.gov, NCT04436471 and NCT04437875. Between June 18 and Aug 3, 2020, we enrolled 76 participants to the two studies (38 in each study). In each study, nine volunteers received rAd26-S in phase 1, nine received rAd5-S in phase 1, and 20 received rAd26-S and rAd5-S in phase 2. Both vaccine formulations were safe and well tolerated. The most common adverse events were pain at injection site (44 [58%]), hyperthermia (38 [50%]), headache (32 [42%]), asthenia (21 [28%]), and muscle and joint pain (18 [24%]). Most adverse events were mild and no serious adverse events were detected. All participants produced antibodies to SARS-CoV-2 glycoprotein. At day 42, receptor binding domain-specific IgG titres were 14 703 with the frozen formulation and 11 143 with the lyophilised formulation, and neutralising antibodies were 49·25 with the frozen formulation and 45·95 with the lyophilised formulation, with a seroconversion rate of 100%. Cell-mediated responses were detected in all participants at day 28, with median cell proliferation of 2·5% CD4+ and 1·3% CD8+ with the frozen formulation, and a median cell proliferation of 1·3% CD4+ and 1·1% CD8+ with the lyophilised formulation. The heterologous rAd26 and rAd5 vector-based COVID-19 vaccine has a good safety profile and induced strong humoral and cellular immune responses in participants. Further investigation is needed of the effectiveness of this vaccine for prevention of COVID-19. Ministry of Health of the Russian Federation.

Adults older than 65 years are at increased risk for atypical presentations of chikungunya disease, as well as for severe outcomes including death. In this phase 3, randomised, double-blind, placebo-controlled, parallel-group trial, adults aged 65 years and older received a single intramuscular dose of Vimkunya (previously chikungunya virus virus-like particle vaccine) or placebo at ten sites in the USA. Participants, clinical site personnel, and the sponsor were masked to individual treatment assignments until all participants had completed their involvement in the trial and the database was cleaned and locked. Baseline and postvaccination chikungunya virus serum neutralising antibody (SNA) titres (NT80) were assessed at selected timepoints. Safety was assessed up to 183 days after dose administration in all participants from the exposed population who provided safety assessment data. This trial is registered with ClinicalTrials.gov, NCT05349617, and is completed. Between May 12 and Dec 2, 2022, 413 participants were recruited and randomly assigned (1:1) to receive the Vimkunya vaccine (n=206) or placebo (n=207). The coprimary endpoints of immunologic superiority of chikungunya virus SNA titres compared with placebo and geometric mean titre at day 22 were met. Vimkunya induced a protective seroresponse (SNA NT80≥100, considered the presumptive seroprotective antibody response) in 149 (82%) of 181 participants (95% CI 76·1–87·2) at day 15, in 165 (87%) of 189 participants (81·8–91·3) at day 22, and in 139 (76%) of 184 participants (68·9–81·2) at day 183. Although there was a slightly higher early immune response in the 65–74 years age group at day 15 compared with the 75 years and older age group, the seroresponse rates at day 22 and day 183 were similar. There were no notable differences in adverse event rates between groups, and most adverse events were grade 1 or 2 in severity and of short duration. No vaccine-related serious adverse events or deaths occurred. We provide robust data from adults aged 65 years and older showing that Vimkunya is well tolerated and can provide a high rate of protection within 2 weeks postvaccination and during 6 months of follow-up. Emergent BioSolutions and Bavarian Nordic.

BCG vaccination provides incomplete protection against tuberculosis in infants. A new vaccine, modified Vaccinia Ankara virus expressing antigen 85A (MVA85A), was designed to enhance the protective efficacy of BCG. We aimed to assess safety, immunogenicity, and efficacy of MVA85A against tuberculosis and Mycobacterium tuberculosis infection in infants. In our double-blind, randomised, placebo-controlled phase 2b trial, we enrolled healthy infants (aged 4–6 months) without HIV infection who had previously received BCG vaccination. We randomly allocated infants (1:1), according to an independently generated sequence with block sizes of four, to receive one intradermal dose of MVA85A or an equal volume of Candida skin test antigen as placebo at a clinical facility in a rural region near Cape Town, South Africa. We actively followed up infants every 3 months for up to 37 months. The primary study outcome was safety (incidence of adverse and serious adverse events) in all vaccinated participants, but we also assessed efficacy in a protocol-defined group of participants who received at least one dose of allocated vaccine. The primary efficacy endpoint was incident tuberculosis incorporating microbiological, radiological, and clinical criteria, and the secondary efficacy endpoint was M tuberculosis infection according to QuantiFERON TB Gold In-tube conversion (Cellestis, Australia). This trial was registered with the South African National Clinical Trials Register (DOH-27-0109-2654) and with ClinicalTrials.gov on July 31, 2009, number NCT00953927 Between July 15, 2009, and May 4, 2011, we enrolled 2797 infants (1399 allocated MVA85A and 1398 allocated placebo). Median follow-up in the per-protocol population was 24·6 months (IQR 19·2–28·1), and did not differ between groups. More infants who received MVA85A than controls had at least one local adverse event (1251 [89%] of 1399 MVA85A recipients and 628 [45%] of 1396 controls who received the allocated intervention) but the numbers of infants with systemic adverse events (1120 [80%] and 1059 [76%]) or serious adverse events (257 [18%] and 258 (18%) did not differ between groups. None of the 648 serious adverse events in these 515 infants was related to MVA85A. 32 (2%) of 1399 MVA85A recipients met the primary efficacy endpoint (tuberculosis incidence of 1·15 per 100 person-years [95% CI 0·79 to 1·62]; with conversion in 178 [13%] of 1398 infants [95% CI 11·0 to 14·6]) as did 39 (3%) of 1395 controls (1·39 per 100 person-years [1·00 to 1·91]; with conversion in 171 [12%] of 1394 infants [10·6 to 14·1]). Efficacy against tuberculosis was 17·3% (95% CI −31·9 to 48·2) and against M tuberculosis infection was −3·8% (–28·1 to 15·9). MVA85A was well tolerated and induced modest cell-mediated immune responses. Reasons for the absence of MVA85A efficacy against tuberculosis or M tuberculosis infection in infants need exploration. Aeras, Wellcome Trust, and Oxford-Emergent Tuberculosis Consortium (OETC).