Safety and efficacy of the intranasal spray SARS-CoV-2 vaccine dNS1-RBD: a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

The live-attenuated influenza virus vector-based intranasal SARS-CoV-2 vaccine (dNS1-RBD, Pneucolin; Beijing Wantai Biological Pharmacy Enterprise, Beijing, China) confers long-lasting and broad protection in animal models and is, to our knowledge, the first COVID-19 mucosal vaccine to enter into human trials, but its efficacy is still unknown. We aimed to assess the safety and efficacy (but not the immunogenicity) of dNS1-RBD against COVID-19. We did a multicentre, randomised, double-blind, placebo-controlled, adaptive design, phase 3 trial at 33 centres (private or public hospitals, clinical research centres, or Centre for Disease Control and Prevention) in four countries (Colombia, Philippines, South Africa, and Viet Nam). Men and non-pregnant women (aged ≥18 years) were eligible if they had never been infected with SARS-CoV-2, and if they did not have a SARS-CoV-2 vaccination history at screening or if they had received at least one dose of other SARS-CoV-2 vaccines 6 months or longer before enrolment. Eligible adults were randomly assigned (1:1) to receive two intranasal doses of dNS1-RBD or placebo administered 14 days apart (0·2 mL per dose; 0·1 mL per nasal cavity), with block randomisation via an interactive web-response system, stratified by centre, age group (18-59 years or ≥60 years), and SARS-CoV-2 vaccination history. All participants, investigators, and laboratory staff were masked to treatment allocation. The primary outcomes were safety of dNS1-RBD in the safety population (ie, those who had received at least one dose of dNS1-RBD or placebo) and efficacy against symptomatic SARS-CoV-2 infection confirmed by RT-PCR occurring 15 days or longer after the second dose in the per-protocol population (ie, those who received two doses, were followed up for 15 days or longer after the second dose, and had no major protocol deviations). The success criterion was predefined as vaccine efficacy of more than 30%. This trial is registered with the Chinese Clinical Trial Registry (ChiCTR2100051391) and is completed. Between Dec 16, 2021, and May 31, 2022, 41 620 participants were screened for eligibility and 31 038 participants were enrolled and randomly assigned (15 517 in the vaccine group and 15 521 in the placebo group). 30 990 participants who received at least one dose (15 496 vaccine and 15 494 placebo) were included in the safety analysis. The results showed a favourable safety profile, with the most common local adverse reaction being rhinorrhoea (578 [3·7%] of 15 500 vaccine recipients and 546 [3·5%] of 15 490 placebo recipients) and the most common systemic reaction being headache (829 [5·3%] vaccine recipients and 797 [5·1%] placebo recipients). We found no differences in the incidences of adverse reactions between participants in the vaccine and placebo groups. No vaccination-related serious adverse events or deaths were observed. Among 30 290 participants who received two doses, 25 742 were included in the per-protocol efficacy analysis (12 840 vaccine and 12 902 placebo). The incidence of confirmed symptomatic SARS-CoV-2 infection caused by omicron variants regardless of immunisation history was 1·6% in the vaccine group and 2·3% in the placebo group, resulting in an overall vaccine efficacy of 28·2% (95% CI 3·4-46·6), with a median follow-up duration of 161 days. Although this trial did not meet the predefined efficacy criteria for success, dNS1-RBD was well tolerated and protective against omicron variants, both as a primary immunisation and as a heterologous booster. Beijing Wantai Biological Pharmacy Enterprise, National Science and Technology Major Project, National Natural Science Foundation of China, Fujian Provincial Science and Technology Plan Project, Natural Science Foundation of Fujian Province, Xiamen Science and Technology Plan Special Project, Bill & Melinda Gates Foundation, the Ministry of Education of China, Xiamen University, and Fieldwork Funds of Xiamen University.

Zhu F ，Huang S ，Liu X ，Chen Q ，Zhuang C ，Zhao H ，Han J ，Jaen AM ，Do TH ，Peter JG ，Dorado AG ，Tirador LS ，Zabat GMA ，Villalobos REM ，Gueco GP ，Botha LLG ，Iglesias Pertuz SP ，Tan J ，Zhu K ，Quan J ，Lin H ，Huang Y ，Jia J ，Chu X ，Chen J ，Chen Y ，Zhang T ，Su Y ，Li C ，Ye X ，Wu T ，Zhang J ，Xia N ，COVID-19-PRO-003 Study Team ... -  《-》

Safety and immunogenicity of the ChAdOx1 nCoV-19 (AZD1222) vaccine against SARS-CoV-2 in people living with and without HIV in South Africa: an interim analysis of a randomised, double-blind, placebo-controlled, phase 1B/2A trial.

People living with HIV are at an increased risk of fatal outcome when admitted to hospital for severe COVID-19 compared with HIV-negative individuals. We aimed to assess safety and immunogenicity of the ChAdOx1 nCoV-19 (AZD1222) vaccine in people with HIV and HIV-negative individuals in South Africa. In this ongoing, double-blind, placebo-controlled, phase 1B/2A trial (COV005), people with HIV and HIV-negative participants aged 18-65 years were enrolled at seven South African locations and were randomly allocated (1:1) with full allocation concealment to receive a prime-boost regimen of ChAdOx1 nCoV-19, with two doses given 28 days apart. Eligibility criteria for people with HIV included being on antiretroviral therapy for at least 3 months, with a plasma HIV viral load of less than 1000 copies per mL. In this interim analysis, safety and reactogenicity was assessed in all individuals who received at least one dose of ChAdOx1 nCov 19 between enrolment and Jan 15, 2021. Primary immunogenicity analyses included participants who received two doses of trial intervention and were SARS-CoV-2 seronegative at baseline. This trial is registered with ClinicalTrials.gov, NCT04444674, and the Pan African Clinicals Trials Registry, PACTR202006922165132. Between June 24 and Nov 12, 2020, 104 people with HIV and 70 HIV-negative individuals were enrolled. 102 people with HIV (52 vaccine; 50 placebo) and 56 HIV-negative participants (28 vaccine; 28 placebo) received the priming dose, 100 people with HIV (51 vaccine; 49 placebo) and 46 HIV-negative participants (24 vaccine; 22 placebo) received two doses (priming and booster). In participants seronegative for SARS-CoV-2 at baseline, there were 164 adverse events in those with HIV (86 vaccine; 78 placebo) and 237 in HIV-negative participants (95 vaccine; 142 placebo). Of seven serious adverse events, one severe fever in a HIV-negative participant was definitely related to trial intervention and one severely elevated alanine aminotranferase in a participant with HIV was unlikely related; five others were deemed unrelated. One person with HIV died (unlikely related). People with HIV and HIV-negative participants showed vaccine-induced serum IgG responses against wild-type Wuhan-1 Asp614Gly (also known as D614G). For participants seronegative for SARS-CoV-2 antigens at baseline, full-length spike geometric mean concentration (GMC) at day 28 was 163·7 binding antibody units (BAU)/mL (95% CI 89·9-298·1) for people with HIV (n=36) and 112·3 BAU/mL (61·7-204·4) for HIV-negative participants (n=23), with a rising day 42 GMC booster response in both groups. Baseline SARS-CoV-2 seropositive people with HIV demonstrated higher antibody responses after each vaccine dose than did people with HIV who were seronegative at baseline. High-level binding antibody cross-reactivity for the full-length spike and receptor-binding domain of the beta variant (B.1.351) was seen regardless of HIV status. In people with HIV who developed high titre responses, predominantly those who were receptor-binding domain seropositive at enrolment, neutralising activity against beta was retained. ChAdOx1 nCoV-19 was well tolerated, showing favourable safety and immunogenicity in people with HIV, including heightened immunogenicity in SARS-CoV-2 baseline-seropositive participants. People with HIV showed cross-reactive binding antibodies to the beta variant and Asp614Gly wild-type, and high responders retained neutralisation against beta. The Bill & Melinda Gates Foundation, South African Medical Research Council, UK Research and Innovation, UK National Institute for Health Research, and the South African Medical Research Council.

Madhi SA ，Koen AL ，Izu A ，Fairlie L ，Cutland CL ，Baillie V ，Padayachee SD ，Dheda K ，Barnabas SL ，Bhorat QE ，Briner C ，Aley PK ，Bhikha S ，Hermanus T ，Horne E ，Jose A ，Kgagudi P ，Lambe T ，Masenya M ，Masilela M ，Mkhize N ，Moultrie A ，Mukendi CK ，Moyo-Gwete T ，Nana AJ ，Nzimande A ，Patel F ，Rhead S ，Taoushanis C ，Thombrayil A ，van Eck S ，Voysey M ，Villafana TL ，Vekemans J ，Gilbert SC ，Pollard AJ ，Moore PL ，Kwatra G ，Wits VIDA COVID team ... -  《Lancet HIV》

Safety and efficacy of PfSPZ Vaccine against malaria in healthy adults and women anticipating pregnancy in Mali: two randomised, double-blind, placebo-controlled, phase 1 and 2 trials.

Plasmodium falciparum parasitaemia during pregnancy causes maternal, fetal, and infant mortality. Poor pregnancy outcomes are related to blood-stage parasite sequestration and the ensuing inflammatory response in the placenta, which decreases over successive pregnancies. A radiation-attenuated, non-replicating, whole-organism vaccine based on P falciparum sporozoites (PfSPZ Vaccine) has shown efficacy at preventing infection in African adults. Here, we aimed to examine vaccine safety and efficacy of the PfSPZ Vaccine in adults and women who anticipated conception. Two randomised, double-blind, placebo-controlled trials (phase 1 MLSPZV3 and phase 2 MLSPZV4) were conducted at a clinical research centre in Mali. MLSPZV3 included adults aged 18-35 years and MLSPZV4 included non-pregnant women aged 18-38 years who anticipated conception within a year of enrolment. In MLSPZV3, participants were stratified by village and randomly assigned (2:1) using block randomisation to receive three doses of 9 × 105 PfSPZ Vaccine or saline placebo at weeks 0, 1, and 4 (4-week schedule) or at weeks 0, 8, and 16 (16-week schedule) and a booster dose around 1 year later. In MLSPZV4, women received presumptive artemether-lumefantrine twice per day for 3 days 2 weeks before dose one and were randomly assigned (1:1:1) using block randomisation to receive three doses of 9 × 105 or 1·8 × 106 PfSPZ Vaccine or saline placebo all administered at weeks 0, 1, and 4 (4-week schedule). Participants in both studies received artemether-lumefantrine 2 weeks before dose three and additionally 2 weeks before dose four (booster dose) in MLSPZV3. Investigators and participants were masked to group assignment. The primary outcome, assessed in the as-treated population, was PfSPZ Vaccine safety and tolerability within 7 days after each dose. The secondary outcome, assessed in the modified intention-to-treat population, was vaccine efficacy against P falciparum parasitaemia (defined as the time-to-first positive blood smear) from dose three until the end of transmission season. In exploratory analyses, MLSPZV4 evaluated incidence of maternal obstetric and neonatal outcomes as safety outcomes, and vaccine efficacy against P falciparum parasitaemia during pregnancy (defined as time-to-first positive blood smear post-conception). In MLSPZV4, women were followed at least once a month with human chorionic gonadotropin testing, and those who became pregnant received standard of care (including intermittent presumptive sulfadoxine-pyrimethamine antimalarial drugs after the first trimester) during routine antenatal visits. These studies are registered with ClinicalTrials.gov, NCT03510481 and NCT03989102. Participants were enrolled for vaccination during the onset of malaria seasons for two sequential studies conducted from 2018 to 2019 for MLSPZV3 and from 2019 to 2021 for MLSPZV4, with follow-up during malaria seasons across 2 years. In MLSPZV3, 478 adults were assessed for eligibility, of whom 220 were enrolled between May 30 and June 12, 2018, and then between Aug 13 and Aug 18, 2018, and 210 received dose one. 66 (96%) of 69 participants who received the 16-week schedule and 68 (97%) of 70 who received the 4-week schedule of the 9 × 105 PfSPZ Vaccine and 70 (99%) of 71 who received saline completed all three doses in year 1. In MLSPZV4, 407 women were assessed for eligibility, of whom 324 were enrolled from July 3 to July 27, 2019, and 320 received dose one of presumptive artemether-lumefantrine. 300 women were randomly assigned with 100 per group (PfSPZ Vaccine 9 × 105, 1·8 × 106, or saline) receiving dose one. First trimester miscarriages were the most commonly reported serious adverse event but occurred at a similar rate across study groups (eight [15%] of 54 with 9 × 105 PfSPZ Vaccine, 12 [21%] of 58 with 1·8 × 106 PfSPZ Vaccine, and five [12%] of 43 with saline). One unrelated maternal death occurred 425 days after the last vaccine dose in the 1·8 × 106 PfSPZ Vaccine group due to peritonitis shortly after childbirth. Most related adverse events reported in MLSPZV3 and MLSPZV4 were mild (grade 1) and frequency of adverse events in the PfSPZ Vaccine groups did not differ from that in the saline group. Two unrelated serious adverse events occurred in MLSPZV3 (one participant had appendicitis in the 9 × 105 PfSPZ Vaccine group and the other in the saline group died due to a road traffic accident). In MLSPZV3, the 9 × 105 PfSPZ Vaccine did not show vaccine efficacy against parasitaemia with the 4-week (27% [95% CI -18 to 55] in year 1 and 42% [-5 to 68] in year 2) and 16-week schedules (16% [-34 to 48] in year 1 and -14% [-95 to 33] in year 2); efficacies were similar or worse against clinical malaria compared with saline. In MLSPZV4, the PfSPZ Vaccine showed significant efficacy against parasitaemia at doses 9 × 105 (41% [15 to 59]; p=0·0069 in year 1 and 61% [36 to 77]; p=0·0011 in year 2) and 1·8 × 106 (54% [34 to 69]; p<0·0001 in year 1 and 45% [13 to 65]; p=0·029 in year 2); and against clinical malaria at doses 9 × 105 (47% [20 to 65]; p=0·0045 in year 1 and 56% [22 to 75]; p=0·0081 in year 2) and 1·8 × 106 (48% [22 to 65]; p=0·0013 in year 1 and 40% [2 to 64]; p=0·069 in year 2). Vaccine efficacy against post-conception P falciparum parasitaemia during first pregnancies that arose in the 2-year follow-up was 57% (14 to 78; p=0·017) in the 9 × 105 PfSPZ Vaccine group versus 49% (3 to 73; p=0·042) in the 1·8 × 106 PfSPZ Vaccine group. Among 55 women who became pregnant within 24 weeks after dose three, vaccine efficacy against parasitaemia was 65% (23 to 84; p=0·0088) with the 9 × 105 PfSPZ Vaccine and 86% (64 to 94; p<0·0001) with the 1·8 × 106 PfSPZ Vaccine. When combined in a post-hoc analysis, women in the PfSPZ Vaccine groups had a non-significantly reduced time-to-first pregnancy after dose one compared with those in the saline group (log-rank test p=0·056). Exploratory maternal obstetric and neonatal outcomes did not differ significantly between vaccine groups and saline. PfSPZ Vaccine was safe and well tolerated in adults in Mali. The 9 × 105 and 1·8 × 106 doses of PfSPZ Vaccine administered as per the 4-week schedule, which incorporated presumptive antimalarial treatment before the first vaccine dose, showed significant efficacy against P falciparum parasitaemia and clinical malaria for two malaria transmission seasons in women of childbearing age and against pregnancy malaria. PfSPZ Vaccine without presumptive antimalarial treatment before the first vaccine dose did not show efficacy. National Institute of Allergy and Infectious Diseases, National Institutes of Health, and Sanaria.

Diawara H ，Healy SA ，Mwakingwe-Omari A ，Issiaka D ，Diallo A ，Traore S ，Soumbounou IH ，Gaoussou S ，Zaidi I ，Mahamar A ，Attaher O ，Fried M ，Wylie BJ ，Mohan R ，Doan V ，Doritchamou JYA ，Dolo A ，Morrison RD ，Wang J ，Hu Z ，Rausch KM ，Zeguime A ，Murshedkar T ，Kc N ，Sim BKL ，Billingsley PF ，Richie TL ，Hoffman SL ，Dicko A ，Duffy PE ，PfSPZ Vaccine Study Team ... -  《-》

Short-term effectiveness of single-dose intranasal spray COVID-19 vaccine against symptomatic SARS-CoV-2 Omicron infection in healthcare workers: a prospective cohort study.

Mi H ，Chen Q ，Lin H ，He T ，Zhang R ，Ren S ，Liu L ，Wang J ，Huang H ，Wang M ，Guo Z ，Su C ... -  《EClinicalMedicine》

Collagenase injection versus limited fasciectomy surgery to treat Dupuytren's contracture in adult patients in the UK: DISC, a non-inferiority RCT and economic evaluation.

Dias J ，Tharmanathan P ，Arundel C ，Welch C ，Wu Q ，Leighton P ，Armaou M ，Corbacho B ，Johnson N ，James S ，Cooke J ，Bainbridge C ，Craigen M ，Warwick D ，Brady S ，Flett L ，Jones J ，Knowlson C ，Watson M ，Keding A ，Hewitt C ，Torgerson D ... -  《-》