In-person and remote recruitment of people with dementia into a primary care-based cluster randomised controlled trial: lessons from the Dementia PersonAlised Care Team (D-PACT) feasibility study (preprint)

Background Recruiting individuals with dementia for clinical trials within primary care is complex, involving socio-cultural, psychological, geographical, and service-related factors. Phase 1 of the Dementia PersonAlised Care Team (D-PACT) study assessed the feasibility of evaluating a personalized dementia support intervention based in primary care in a cluster randomized controlled trial. COVID-19 necessitated a shift to remote working, providing the opportunity to compare in-person and remote capacity judgment and recruitment.Methods Using an inclusive multi-stage approach, in-person recruitment commenced September 2019 but was temporarily halted in March 2020 due to COVID-19. The study resumed recruitment remotely from September 2020 to March 2021. We analysed quantitative data comparing both periods, examining proportion of recruited GP practices and participants, participant recruitment rate per month and number of meetings/time required for consent and baseline. Qualitative interviews explored participants’ experiences of remote recruitment using thematic analysis.Results Pre-COVID-19, 61.5% (n = 8) of approached GP practices (n = 13) were recruited vs. 20% (n = 4) during COVID-19. In-person participant recruitment yielded 9.9% (22 recruited/228 approached), while remote recruitment achieved 17.2% (n = 34). 15 of the 34 had been approached prior to COVID-19, put on hold but re-approached/recruited remotely post-study pause. Even accounting for this, remote recruitment remained comparable at 9.6% (19/198). Monthly recruitment rate increased from 3.6 dyads in-person to 5.6 remotely. However mean time on recruitment was higher (9 hours per participant in-person vs.15 remotely), and time on specific activities differed: no travel time during COVID-19, offset by increased preparation/administration. Our multi-stage approach added to overall recruitment time but proved productive, achieving recruitment percentages of 40%, 39%, and 23% respectively from interested patients. Qualitative interviews (n = 13) indicated general acceptability of remote recruitment, with preferences tied to individual needs.Conclusions Our findings contribute to recruitment strategies for primary care trials by showing remotely judging capacity and recruiting people with dementia without specialist support using person-centred approaches is possible. While time-intensive, recruitment rates were not compromised. Researchers should consider flexible, hybrid approaches to increase participation. Understanding the time commitment essential for inclusive dementia recruitment will guide realistic target setting and study design. Funders should consider time and financial requirements in their decisions.Trial registration: ISRCTN80204146. Registration date 23/09/2019

The discovery of gene mutations making SARS-CoV-2 well adapted for humans: host-genome similarity analysis of 2594 genomes from China, the USA and Europe (preprint)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a positive-sense single-stranded virus approximately 30 kb in length, causes the ongoing novel coronavirus disease-2019 (COVID-19). Studies confirmed significant genome differences between SARS-CoV-2 and SARS-CoV, suggesting that the distinctions in pathogenicity might be related to genomic diversity. However, the relationship between genomic differences and SARS-CoV-2 fitness has not been fully explained, especially for open reading frame (ORF)-encoded accessory proteins. RNA viruses have a high mutation rate, but how SARS-CoV-2 mutations accelerate adaptation is not clear. This study shows that the host-genome similarity (HGS) of SARS-CoV-2 is significantly higher than that of SARS-CoV, especially in the ORF6 and ORF8 genes encoding proteins antagonizing innate immunity in vivo . A power law relationship was discovered between the HGS of ORF3b, ORF6, and N and the expression of interferon (IFN)-sensitive response element (ISRE)-containing promoters. This finding implies that high HGS of SARS-CoV-2 genome may further inhibit IFN I synthesis and cause delayed host innate immunity. An ORF1ab mutation, 10818G>T, which occurred in virus populations with high HGS but rarely in low-HGS populations, was identified in 2594 genomes with geolocations of China, the USA and Europe. The 10818G>T caused the amino acid mutation M37F in the transmembrane protein nsp6. The results suggest that the ORF6 and ORF8 genes and the mutation M37F may play important roles in causing COVID-19. The findings demonstrate that HGS analysis is a promising way to identify important genes and mutations in adaptive strains, which may help in searching potential targets for pharmaceutical agents.

A Single Dose of Self-Transcribing and Replicating RNA Based SARS-CoV-2 Vaccine Produces Protective Adaptive Immunity In Mice (preprint)

A self-transcribing and replicating RNA (STARR) based vaccine (LUNAR-COV19) has been developed to prevent SARS-CoV-2 infection. The vaccine encodes an alphavirus-based replicon and the SARS-CoV-2 full length spike glycoprotein. Translation of the replicon produces a replicase complex that amplifies and prolong SARS-CoV-2 spike glycoprotein expression. A single prime vaccination in mice led to robust antibody responses, with neutralizing antibody titers increasing up to day 60. Activation of cell mediated immunity produced a strong viral antigen specific CD8+ T lymphocyte response. Assaying for intracellular cytokine staining for IFN-gamma; and IL-4 positive CD4+ T helper lymphocytes as well as anti-spike glycoprotein IgG2a/IgG1 ratios supported a strong Th1 dominant immune response. Finally, single LUNAR-COV19 vaccination at both 2 microgram and 10 microgram doses completely protected human ACE2 transgenic mice from both mortality and even measurable infection following wild-type SARS-CoV-2 challenge. Our findings collectively suggest the potential of Lunar-COV19 as a single dose vaccine.