Immunogenicity and Safety of Heterologous Omicron BA.1 and Bivalent SARS-CoV-2 Recombinant Spike Protein Booster Vaccines: A Phase 3 Randomized Clinical Trial.

BACKGROUND: Mutations present in emerging SARS-CoV-2 variants permit evasion of neutralization with prototype vaccines. A novel Omicron BA.1 subvariant-specific vaccine (NVX-CoV2515) was tested alone or as a bivalent preparation with the prototype vaccine (NVX-CoV2373) to assess antibody responses to SARS-CoV-2. METHODS: Participants aged 18 to 64 years immunized with 3 doses of prototype mRNA vaccines were randomized 1:1:1 to receive a single dose of NVX-CoV2515, NVX-CoV2373, or the bivalent mixture in a phase 3 study investigating heterologous boosting with SARS-CoV-2 recombinant spike protein vaccines. Immunogenicity was measured 14 and 28 days after vaccination for the SARS-CoV-2 Omicron BA.1 sublineage and ancestral strain. Safety profiles of vaccines were assessed. RESULTS: Of participants who received trial vaccine (N = 829), those administered NVX-CoV2515 (n = 286) demonstrated a superior neutralizing antibody response to BA.1 vs NVX-CoV2373 (n = 274) at day 14 (geometric mean titer ratio, 1.6; 95% CI, 1.33-2.03). Seroresponse rates were 73.4% (91/124; 95% CI, 64.7-80.9) for NVX-CoV2515 vs 50.9% (59/116; 95% CI, 41.4-60.3) for NVX-CoV2373. All formulations were similarly well tolerated. CONCLUSIONS: NVX-CoV2515 elicited a superior neutralizing antibody response against the Omicron BA.1 subvariant as compared with NVX-CoV2373 when administered as a fourth dose. Safety data were consistent with the established safety profile of NVX-CoV2373. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov (NCT05372588).

Annual hepatitis C testing and positive tests among gay and bisexual men in Australia from 2016 to 2022: a serial cross-sectional analysis of sentinel surveillance data.

OBJECTIVE: Guidelines recommend annual hepatitis C virus (HCV) testing for gay and bisexual men (GBM) with HIV and GBM prescribed HIV pre-exposure prophylaxis (PrEP). However, there is a limited understanding of HCV testing among GBM. We aimed to examine trends in HCV testing and positivity from 2016 to 2022. METHODS: Using sentinel surveillance data, we examined the proportion of GBM with at least one test and the proportion with a positive test in each year for HCV antibody testing among GBM with no previous HCV positive test, HCV RNA testing among GBM with a positive antibody test but no previous positive RNA test (naïve RNA testing), and HCV RNA testing among people who had a previous RNA positive test and a subsequent negative test (RNA follow-up testing). Trends were examined using logistic regression from 2016 to 2019 and 2020 to 2022. RESULTS: Among GBM with HIV, from 2016 to 2019 antibody testing was stable averaging 55% tested annually. Declines were observed for both naïve HCV RNA testing (75.4%-41.4%: p<0.001) and follow-up HCV RNA testing (70.1%-44.5%: p<0.001). Test positivity declined for HCV antibody tests (2.0%-1.3%: p=0.001), HCV RNA naïve tests (75.4%-41.4%: p<0.001) and HCV RNA follow-up tests (11.3%-3.3%: p=0.001). There were minimal or no significant trends from 2020 to 2022.Among GBM prescribed PrEP, antibody testing declined from 2016 to 2019 (79.4%-69.4%: p<0.001) and was stable from 2020 to 2022. Naïve and follow-up HCV RNA testing was stable with an average of 55% and 60% tested each year, respectively. From 2016-2019, the proportion positive from HCV RNA naïve tests declined (44.1%-27.5%: p<0.046) with no significant change thereafter. Positive follow-up HCV RNA tests fluctuated with no or one new positive test among this group in most years. CONCLUSION: The proportion of GBM with positive HCV tests has declined, however a substantial proportion are not tested annually. A renewed focus on HCV testing, and treatment where required, is warranted to achieve HCV elimination among GBM in Australia.

Hepatitis C virus reinfection incidence among gay and bisexual men with HIV in Australia from 2016 to 2020.

BACKGROUND: There is some concern that hepatitis C virus (HCV) reinfection might impact HCV micro-elimination efforts among gay and bisexual men (GBM) with HIV. However, there is a limited understanding of reinfection incidence in the context of unrestricted government-funded HCV treatment. We aimed to estimate HCV reinfection incidence among GBM with HIV in Australia from 2016 to 2020. METHODS: Data were from 39 clinics participating in ACCESS, a sentinel surveillance network for blood borne viruses and sexually transmissible infections across Australia. GBM with HIV who had evidence of treatment or spontaneous clearance with at least one positive HCV RNA test, a subsequent negative HCV RNA test, and at least one additional HCV RNA test between 1st January 2016 and 31st December 2020 were eligible for inclusion. A new HCV RNA positive test and/or detectable viral load was defined as a reinfection. Generalised linear modelling was used to examine trends in reinfection. RESULTS: Among 12 213 GBM with HIV who had at least one HCV test, 540 were included in the reinfection incidence analysis, of whom 38 (7%) had evidence of reinfection during the observation period. Over 1124 person-years of follow-up, the overall rate of reinfection was 3.4/100PY (95% CI 2.5-4.6). HCV reinfection incidence declined on average 30% per calendar year (Incidence Rate Ratio 0.70, 95% CI 0.54-0.91). CONCLUSION: HCV reinfection incidence has declined among GBM with HIV in Australia since government-funded unrestricted DAAs were made available. Ongoing HCV RNA testing following cure and prompt treatment for anyone newly diagnosed is warranted to sustain this.

Condom Failure Among HIV-Negative Men in Serodiscordant Relationships in Australia, Brazil, and Thailand.

Condoms continue to be used by many gay, bisexual, and other men who have sex with men (GBM) to reduce the risk of HIV transmission. However this is impacted by condom failure events, defined here as condom breakage and slippage. In a prospective, observational cohort study of 343 HIV serodiscordant male couples recruited through high HIV caseload clinics and hospitals between 2012 and 2016 in Australia, Brazil, and Thailand, condom failure rates and associated factors were analysed, including with the study partner versus other sexual partners. There were 717 reported instances of condom failure from an estimated total of 25,831 sex acts with condoms, from over 588.4 participant years of follow up. Of the HIV-negative partners (n = 343) in the study, more than a third (n = 117, 36.7%) reported at least one instance of condom failure with any partner type during study follow-up. Condom failure with their study partner was reported by 91/343 (26.5%) HIV-negative partners, compared with 43/343 (12.5%) who reported condom failure with other partners. In total, there were 86 events where the HIV-negative partner experienced ano-receptive condom failure with ejaculation, representing 12.0% of all failure events. In multivariable analysis, compared to Australia, HIV-negative men in Brazil reported a higher incidence risk rate of condom failure (IRR = 1.64, 95%CI 1.01-2.68, p = 0.046) and HIV-negative men who reported anal sex with other partners reported an increased risk of condom failure compared with men who only had sex with their study partner (IRR = 1.89, 95%CI 1.08-3.33, p = 0.025). Although at least one event of condom failure was reported by a significant proportion of participants, overall condom failure events represented a small proportion of the total condom protected sex acts.

Tricaprilin (CER-0001) for the preventive treatment of migraine: A phase 2 randomised, double-blind, placebo-controlled pilot study.

BACKGROUND: Increasing evidence indicates a metabolic etiology for migraines, with ketosis potentially rectifying metabolic and clinical features. We conducted a pilot study to evaluate CER-0001, a ketogenic agent, for migraine prevention without dietary changes. METHODS: This was a 2-part, double-blind, randomised, placebo-controlled study conducted in Australia. Adults with at least a 1-year history of migraine and ≥ 1 prior preventive treatment failure were randomised to either oral CER-0001 (up to 30 g twice a day) or placebo for 12 weeks. The primary endpoint was Month 3 change in Migraine Headache Days from baseline. RESULTS: Part 1 results are presented. 81 participants were randomised and dosed (n = 40 CER-0001, n = 41 placebo), and 61 participants had evaluable efficacy data. No statistically significant difference was observed in the primary endpoint (LSMean difference 0.92 days; p = 0.586). During Month 2, a mean improvement of -2.8 days was observed for CER-0001 (p = 0.056). Withdrawal rates were 45.0% and 53.7% (CER-0001; placebo). The proportion of participants reporting at least one treatment-emergent adverse event was similar between arms (90.0% CER-0001, 82.9% placebo), mostly gastrointestinal (85.0% CER-0001, 70.7% placebo). CONCLUSION: Results suggest positive directional promise over 2-3 months for CER-0001. A new formulation will be used for larger, fully powered phase 2/3 studies. TRIAL REGISTRATION: This study is registered at ClinicalTrials.gov (NCT04437199).

Risk of Primary Incident Hepatitis C Infection Following Bacterial Sexually Transmissible Infections Among Gay and Bisexual Men in Australia From 2016 to 2020.

Background: In Australia, the incidence of hepatitis C virus (HCV) has declined among gay and bisexual men (GBM) with human immunodeficiency virus (HIV) since 2015 and is low among GBM using HIV preexposure prophylaxis (PrEP). However, ongoing HCV testing and treatment remains necessary to sustain this. To assess the potential utility of sexually transmissible infections (STIs) to inform HCV testing among GBM with HIV and GBM using PrEP, we examined the association between bacterial STI diagnoses and subsequent primary HCV infection. Methods: Data were from a national network of 46 clinics participating in the Australian Collaboration for Coordinated Enhanced Sentinel Surveillance. GBM included had ≥1 HCV antibody negative test result and ≥1 subsequent HCV antibody and/or RNA test. Discrete time survival analysis was used to estimate the association between a positive syphilis, rectal chlamydia, and rectal gonorrhea diagnosis in the previous 2 years and a primary HCV diagnosis, defined as a positive HCV antibody or RNA test result. Results: Among 6529 GBM with HIV, 92 (1.4%) had an incident HCV infection. A prior positive syphilis diagnosis was associated with an incident HCV diagnosis (adjusted hazard ratio, 1.99 [95% confidence interval, 1.11-3.58]). Among 13 061 GBM prescribed PrEP, 48 (0.4%) had an incident HCV diagnosis. Prior rectal chlamydia (adjusted hazard ratio, 2.75 [95% confidence interval, 1.42-5.32]) and rectal gonorrhea (2.54 [1.28-5.05]) diagnoses were associated with incident HCV. Conclusions: Diagnoses of bacterial STIs in the past 2 years was associated with HCV incidence. These findings suggest that STIs might be useful for informing HCV testing decisions and guidelines for GBM with HIV and GBM using PrEP.

Immunogenicity and safety of a bivalent (omicron BA.5 plus ancestral) SARS-CoV-2 recombinant spike protein vaccine as a heterologous booster dose: interim analysis of a phase 3, non-inferiority, randomised, clinical trial.

BACKGROUND: SARS-CoV-2 variants evade immunity despite vaccination with prototype COVID-19 vaccines or previous infection. The 2019nCoV-311 (part 2) study is evaluating immune responses after two booster doses of a vaccine containing the omicron BA.5 subvariant spike protein in adults previously vaccinated with a prototype mRNA vaccine. This interim analysis reports on day 28 immunogenicity and safety outcomes after one booster dose. METHODS: In this phase 3, randomised, observer-blinded study conducted at 35 sites in Australia, medically stable, previously COVID-19-vaccinated (mRNA-based; ≥three doses) adults aged 18 years or older were enrolled and randomly allocated (1:1:1; via an interactive web response system) to receive two doses of bivalent (NVX-CoV2373 + NVX-CoV2540; bivalent group), authorised prototype (NVX-CoV2373; prototype group), or BA.5 (NVX-CoV2540; BA.5 group) vaccine. Only blinded personnel performed study assessments or had participant contact to collect data after study vaccination. Participants received vaccines containing 5 µg SARS-CoV-2 recombinant spike protein and 50 µg Matrix-M adjuvant, administered via a 0·5 mL intramuscular injection (2·5 µg of NVX-CoV2373 plus 2·5 µg of NVX-CoV2540 for the bivalent vaccine, prepared on-site as a 1:1 mixture). The coprimary endpoints include day 28 neutralising antibody geometric mean titre (GMT) ratios (GMTRs) to omicron BA.5 and the ancestral strain, and seroresponse rates to BA.5, in the bivalent and prototype groups. These endpoints were calculated in the per-protocol analysis set, which was defined as participants who had received a vaccine dose, had baseline and day 28 immunogenicity data, and were PCR-negative for SARS-CoV-2, with no major protocol deviations. The primary objective was to determine the primary outcome (antibody responses), which consisted of three comparisons: superiority of the bivalent versus prototype vaccine for neutralising antibody GMT to BA.5 (ie, lower bound of the GMTR 95% CI >1·0); non-inferiority of neutralising antibody seroresponse rate to BA.5 (ie, lower bound of the seroresponse rate 95% CI >-5%); and non-inferiority of neutralising antibody GMT to the ancestral strain (ie, lower bound of GMTR 95% CI >0·67). This trial was registered at ClinicalTrials.gov, number NCT05372588. FINDINGS: Between March 22, 2023 and May 2, 2023, 837 participants were screened for eligibility and 766 were randomly allocated to receive the BA.5 (n=255), prototype (n=252), or bivalent (n=259) vaccine. After accounting for exclusions due to participants being baseline SARS-CoV-2-positive, having previous infection, or protocol deviations, the per-protocol analysis set included 694 participants (236 in BA.5 group, 227 in prototype group, and 231 in bivalent group). In this interim analysis (maximum follow-up 35 days after the first dose), the bivalent group, compared with the prototype group, had superior neutralising antibody responses to BA.5 (GMT 1017·8 [95% CI 891·0-1162·6] vs 515·1 [450·4-589·0]; GMTR 2·0 [1·69-2·33]) and a non-inferior seroresponse rate to BA.5 at day 28 (39·8% [33·5-46·5] vs 12·3% [8·4-17·3]; difference 27·5% [19·8-35·0]). The bivalent group also had non-inferior neutralising antibody responses to the ancestral strain (GMTR 1·0 [0·84-1·20]), compared with the prototype group. All vaccines were similarly well tolerated. INTERPRETATION: All three coprimary endpoints were met in part 2 of the ongoing 2019nCoV-311 study. These data support the development of monovalent and/or bivalent vaccines for the most currently circulating variants, to optimise protection. With no new safety findings, further investigation of omicron-based subvariant vaccines is supported by the evidence. FUNDING: Novavax.