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The APOBEC3 proteins form a multigene family of cytidine deaminases with inhibitory activity against viruses and retrotransposons. In contrast to APOBEC3G (A3G), APOBEC3A (A3A) has no effect on lentiviruses but dramatically inhibits replication of the parvovirus adeno-associated virus (AAV). To study the contribution of deaminase activity to the antiviral activity of A3A, we performed a comprehensive mutational analysis of A3A. By mutation of non-conserved residues, we found that regions outside of the catalytic active site contribute to both deaminase and antiviral activities. Using A3A point mutants and A3A/A3G chimeras, we show that deaminase activity is not required for inhibition of recombinant AAV production. We also found that deaminase-deficient A3A mutants block replication of both wild-type AAV and the autonomous parvovirus minute virus of mice (MVM). In addition, we identify specific residues of A3A that confer activity against AAV when substituted into A3G. In summary, our results demonstrate that deaminase activity is not necessary for the antiviral activity of A3A against parvoviruses.

Humoral immunodeficiency patients require immunoglobulin replacement to prevent infection. Traditional intravenous immunoglobulin manufacturing methods have had the potential for containing impurities caused by physical, chemical and thermal stressors that alter proteins. Two intravenous immunoglobulin products, BIVIGAM® and ASCENIV™, are manufactured by a modified Cohn-Oncley fractionation method followed by chromatographic purification. These products have undergone a systematic quality by design optimization to identify critical manufacturing processes to produce the highest quality product. This data driven, small-scale approach has led to manufacturing enhancements that have yielded consistent product improvements. The systematic approach to optimizing manufacturing has guided process changes, in-process, procedural and engineering controls that have reduced protein shearing and aggregation, and improved purity resulting in products with lot-to-lot consistency.

Licensed mRNA COVID-19 vaccines require booster doses to sustain SARS-CoV-2-specific responses, creating the need for novel, broadly immunogenic vaccines. We aimed to compare the immunogenicity, safety, and tolerability of ARCT-154—a self-amplifying mRNA vaccine against SARS-CoV-2 D614G variant—with the BNT162b2 (Comirnaty; Pfizer–BioNTech) mRNA vaccine when administered as a fourth-dose booster. This double-blind, multicentre, randomised, controlled, phase 3, non-inferiority trial, conducted at 11 outpatient clinical sites in Japan, enrolled healthy adults aged at least 18 years who had previously been immunised with two doses of an mRNA COVID-19 vaccine (BNT162b2 or mRNA-1273 [Spikevax; Moderna]) followed by a third dose of BNT162b2 at least 3 months before enrolment. Participants were randomly assigned, in a 1:1 ratio using an Interactive Response Technology system with a block size of four, and with stratification by age (18–64 years or ≥65 years) and by interval since last COVID-19 vaccination (<5 months or ≥5 months), to receive either ARCT-154 or BNT162b2 as a fourth-dose booster via deltoid intramuscular injection. Participants and investigators assessing outcomes were masked to group assignment. The primary objective, measured in per-protocol set 1 (consisting of participants with no evidence of previous SARS-CoV-2 infection who received their intended injection according to protocol), was to show that the immune response 28 days after the ARCT-154 vaccine was non-inferior to that of the BNT162b2 vaccine, measured in terms of both pseudovirus neutralising antibody geometric mean titre (GMT) ratios and seroresponse rates against the wild-type Wuhan-Hu-1 strain of SARS-CoV-2. Non-inferiority was declared when the lower limit of the 95% CI of the ARCT-154 to BNT162b2 GMT ratio exceeded 0·67, and when the lower limit for the difference in seroresponse rates exceeded −10%. Key secondary endpoints included the immune response against the omicron BA.4/5 subvariant, which was assessed for non-inferiority and superiority in per-protocol set 1. Safety was assessed in the full analysis set. This study was registered on the Japan Registry for Clinical Trials, jRCT 2071220080, and is ongoing. Between Dec 13, 2022, and Feb 25, 2023, we enrolled and randomly assigned 828 participants to receive ARCT-154 (n=420) or BNT162b2 (n=408) vaccines as a fourth-dose booster. In per-protocol set 1, the GMTs of surrogate neutralising antibodies induced against the Wuhan-Hu-1 SARS-CoV-2 strain in the ARCT-154 group (5641 [95% CI 4321–7363]) were non-inferior to those in the BNT162b2 group (3934 [2993–5169]) when measured at 28 days after boosting, with a GMT ratio of 1·43 (95% CI 1·26–1·63). Seroresponse rates were 65·2% (95% CI 60·2–69·9) in the ARCT-154 group versus 51·6% (46·4–56·8) in the BNT162b2 group, a difference of 13·6% (95% CI 6·8–20·5). GMTs against the omicron BA.4/5 variant on day 29 were 2551 (1687–3859) in the ARCT-154 group and 1958 (1281–2993) in the BNT162b2 group—a GMT ratio of 1·30 (1·07–1·58)—with seroresponse rates of 69·9% (65·0–74·4) and 58·0% (52·8–63·1). Both boosters were equally well tolerated. No treatment-related deaths were reported, nor were there severe or serious adverse events considered to be causally associated related to study vaccination. One serious adverse event, a foot deformity reported in a participant in the BNT162b2 group, was observed but determined not to have a causal relationship to the study vaccination. One severe adverse event, a case of abnormal hepatic function in the ARCT-154 group, was considered to be related to study vaccine. Adverse events of special interest for detection of myocarditis and pericarditis included chest pain (one case in the ARCT-154 group and three cases in the BNT162b2 group) and shortness of breath (two cases in the BNT162b2 group), all of which were considered to have a reasonable possibility of being related to vaccination. Local reactions were reported by 398 (95%) of 420 participants receiving the ARCT-154 vaccine and 395 (97%) of 408 participants receiving the BNT162b2 vaccine, and solicited systemic adverse events by 276 (66%) of those receiving the ARCT-154 vaccine and 255 (63%) of those receiving the BNT162b2 vaccine. Adverse events were mainly mild in severity, occurring and resolving within 3–4 days after vaccination. In adults who had previously received three doses of an mRNA COVID-19 vaccine, immune responses 28 days after an ARCT-154 booster dose were non-inferior to those observed after a BNT162b2 booster dose for the Wuhan-Hu-1 strain of SARS-CoV-2 and superior for the Omicron BA.4/5 variant. Increased immune responses at 28 days might provide increased likelihood of protection against these strains during this period and could also result in longer duration of protection. Further studies will assess the immunogenicity induced against more recent SARS-CoV-2 variants. Japanese Ministry of Health, Labour, and Welfare. For the Japanese translation of the abstract see Supplementary Materials section.

Combination of waning immunity and lower effectiveness against new SARS-CoV-2 variants of approved COVID-19 vaccines necessitates new vaccines. We evaluated two doses, 28 days apart, of ARCT-154, a self-amplifying mRNA COVID-19 vaccine, compared with saline placebo in an integrated phase 1/2/3a/3b controlled, observer-blind trial in Vietnamese adults (ClinicalTrial.gov identifier: NCT05012943). Primary safety and reactogenicity outcomes were unsolicited adverse events (AE) 28 days after each dose, solicited local and systemic AE 7 days after each dose, and serious AEs throughout the study. Primary immunogenicity outcome was the immune response as neutralizing antibodies 28 days after the second dose. Efficacy against COVID-19 was assessed as primary and secondary outcomes in phase 3b. ARCT-154 was well tolerated with generally mild–moderate transient AEs. Four weeks after the second dose 94.1% (95% CI: 92.1–95.8) of vaccinees seroconverted for neutralizing antibodies, with a geometric mean-fold rise from baseline of 14.5 (95% CI: 13.6–15.5). Of 640 cases of confirmed COVID-19 eligible for efficacy analysis most were due to the Delta (B.1.617.2) variant. Efficacy of ARCT-154 was 56.6% (95% CI: 48.7– 63.3) against any COVID-19, and 95.3% (80.5–98.9) against severe COVID-19. ARCT-154 vaccination is well tolerated, immunogenic and efficacious, particularly against severe COVID-19 disease. In this randomized, controlled integrated phase 1/2/3a/3b clinical trial, the authors show that the self-amplifying mRNA COVID-19 vaccine ARCT-154 shows good immunogenicity and is safe and efficient against COVID-19 (57% against any COVID-19, and 95% against severe COVID-19).

The APOBEC3 proteins form a multigene family of cytidine deaminases with inhibitory activity against viruses and retrotransposons. In contrast to APOBEC3G (A3G), APOBEC3A (A3A) has no effect on lentiviruses but dramatically inhibits replication of the parvovirus adeno-associated virus (AAV). To study the contribution of deaminase activity to the antiviral activity of A3A, we performed a comprehensive mutational analysis of A3A. By mutation of non-conserved residues, we found that regions outside of the catalytic active site contribute to both deaminase and antiviral activities. Using A3A point mutants and A3A/A3G chimeras, we show that deaminase activity is not required for inhibition of recombinant AAV production. We also found that deaminase-deficient A3A mutants block replication of both wild-type AAV and the autonomous parvovirus minute virus of mice (MVM). In addition, we identify specific residues of A3A that confer activity against AAV when substituted into A3G. In summary, our results demonstrate that deaminase activity is not necessary for the antiviral activity of A3A against parvoviruses.

This paper describes a two-cycle bacteria energy recovery system (BERS) to power two embedded sensors: an ultra-low portable pH sensor and a sound sensor. The designed unit can handle up to seven microbial fuel cells (MFCs) to charge a super-capacitor. This allows the BERS to provide a constant 0.14 mW without further electrical components for signal conditioning. The two cycles were driven with a 100 kΩ load and a 10 Hz frequency. The BERS is also self-powered with an integrated start-up unit to be self-activated when the MFCs charge the energy-storing unit after three days. The BERS powered pH sensor has an error below 5% at 25 ∘C and is able to work continuously while being activated for 4 h. The performances of the pH and sound sensors were determined based on a compromise between accuracy and power consumption.

The “3 by 5” goal to have 3 million people in low and middle income countries on antiretroviral therapy (ART) by the end of 2005 is ambitious. Estimates of the necessary resources are needed to facilitate resource mobilisation and rapid channelling of funds to where they are required. We estimated the financial costs needed to implement treatment protocols, by use of country-specific estimates for 34 countries that account for 90% of the need for ART in resource-poor settings. We first estimated the number of people needing ART and supporting programmes for each country. We then estimated the cost per patient for each programme by country to derive total costs. We estimate that between US$5·1 billion and US$5·9 billion will be needed by the end of 2005 to provide ART, support programmes, and cover country-level administrative and logistic costs for 3 by 5.