Vaccine effectiveness against hospital admission in South African health care workers who received a homologous booster of Ad26.COV2 during an Omicron COVID19 wave: Preliminary Results of the Sisonke 2 Study.

Following the results of the ENSEMBLE 2 study, which demonstrated improved vaccine efficacy of a two-dose regimen of Ad26.COV.2 vaccine given 2 months apart, we expanded the Sisonke study which had provided single dose Ad26.COV.2 vaccine to almost 500 000 health care workers (HCW) in South Africa to include a booster dose of the Ad26.COV.2. Sisonke 2 enrolled 227 310 HCW from the 8 November to the 17 December 2021. Enrolment commenced before the onset of the Omicron driven fourth wave in South Africa affording us an opportunity to evaluate early VE in preventing hospital admissions of a homologous boost of the Ad26.COV.2 vaccine given 6-9 months after the initial vaccination in HCW. We estimated vaccine effectiveness (VE) of the Ad26.COV2.S vaccine booster in 69 092 HCW as compared to unvaccinated individuals enrolled in the same managed care organization using a test negative design. We compared VE against COVID19 admission for omicron during the period 15 November to 20 December 2021. After adjusting for confounders, we observed that VE for hospitalisation increased over time since booster dose, from 63% (95%CI 31-81%); to 84% (95% CI 67-92%) and then 85% (95% CI: 54-95%), 0-13 days, 14-27 days, and 1-2 months post-boost. We provide the first evidence of the effectiveness of a homologous Ad26.COV.2 vaccine boost given 6-9 months after the initial single vaccination series during a period of omicron variant circulation. This data is important given the increased reliance on the Ad26.COV.2 vaccine in Africa.

High Rate of Asymptomatic Carriage Associated with Variant Strain Omicron

The early widespread dissemination of Omicron indicates the urgent need to better understand the transmission dynamics of this variant, including asymptomatic spread among immunocompetent and immunosuppressed populations. In early December 2021, the Ubuntu clinical trial, designed to evaluate efficacy of the mRNA-1273 vaccine (Moderna) among persons living with HIV (PLWH), began enrolling participants. Nasal swabs are routinely obtained at the initial vaccination visit, which requires participants to be clinically well to receive their initial jab. Of the initial 230 participants enrolled between December 2 and December 17, 2021, 71 (31%) were PCR positive for SARS-CoV-2: all of whom were subsequently confirmed by S gene dropout to be Omicron; 48% of the tested samples had cycle threshold (CT) values <25 and 18% less than 20, indicative of high titers of asymptomatic shedding. Asymptomatic carriage rates were similar in SARS-CoV-2 seropositive and seronegative persons (27% respectively). These data are in stark contrast to COVID-19 vaccine studies conducted pre-Omicron, where the SARS-CoV-2 PCR positivity rate at the first vaccination visit ranged from <1%-2.4%, including a cohort of over 1,200 PLWH largely enrolled in South Africa during the Beta outbreak. We also evaluated asymptomatic carriage in a sub study of the Sisonke vaccine trial conducted in South African health care workers, which indicated 2.6% asymptomatic carriage during the Beta and Delta outbreaks and subsequently rose to 16% in both PLWH and PHLWH during the Omicron period. These findings strongly suggest that Omicron has a much higher rate of asymptomatic carriage than other VOC and this high prevalence of asymptomatic infection is likely a major factor in the widespread, rapid dissemination of the variant globally, even among populations with high prior rates of SARS-COV-2 infection.

Safety of the single-dose Ad26.CoV2.S vaccine among healthcare workers in the phase 3b Sisonke study in South Africa

BackgroundThe Sisonke open-label phase 3b implementation study aimed to assess the safety and effectiveness of the Janssen Ad26.CoV2.S vaccine among health care workers (HCWs) in South Africa. Here, we present the safety data. MethodsWe monitored adverse events (AEs) at vaccination sites, through self-reporting triggered by text messages after vaccination, health care provider reports and by active case finding. The frequency and incidence rate of non-serious and serious AEs were evaluated from day of first vaccination (17 February 2021) until 28 days after the final vaccination (15 June 2021). COVID-19 breakthrough infections, hospitalisations and deaths were ascertained via linkage of the electronic vaccination register with existing national databases. FindingsOf 477,234 participants, 10,279 (2.2%) reported AEs, of which 139 (1.4%) were serious. Women reported more AEs than men (2.3% vs. 1.6%). AE reports decreased with increasing age (3.2% for 18-30, 2.1% for 31-45, 1.8% for 46-55 and 1.5% in >55-year-olds). Participants with previous COVID-19 infection reported slightly more AEs (2.6% vs. 2.1%). The commonest reactogenicity events were headache and body aches, followed by injection site pain and fever, and most occurred within 48 hours of vaccination. Two cases of Thrombosis with Thrombocytopenia Syndrome and four cases of Guillain-Barre Syndrome were reported post-vaccination. Serious AEs and AEs of special interest including vascular and nervous system events, immune system disorders and deaths occurred at lower than the expected population rates. InterpretationThe single-dose Ad26.CoV2.S vaccine had an acceptable safety profile supporting the continued use of this vaccine in our setting. FundingFunding was provided by the National Treasury of South Africa, the National Department of Health, Solidarity Response Fund NPC, The Michael & Susan Dell Foundation, The Elma Vaccines and Immunization Foundation - Grant number 21-V0001, and the Bill & Melinda Gates Foundation - grant number INV-030342.

Immunogenicity of the Ad26.CoV2.S vaccine in people living with HIV

BackgroundPeople living with HIV (PLWH) have been reported to have an increased risk of more severe COVID-19 disease outcome and an increased risk of death relative to HIV-uninfected individuals. Here we assessed the ability of the Johnson and Johnson Ad26.CoV2.S vaccine to elicit neutralizing antibodies to the Delta variant in PLWH relative to HIV-uninfected individuals. We also compared the neutralization after vaccination to neutralization elicited by SARS-CoV-2 infection only in HIV-uninfected, suppressed HIV PLWH, and PLWH with detectable HIV viremia. MethodsWe enrolled 26 PLWH and 73 HIV-uninfected participants from the SISONKE phase 3b open label South African clinical trial of the Ad26.CoV2.S vaccine in health care workers (HCW). Enrollment was a median 56 days (range 19-98 days) post-vaccination and PLWH in this group had well controlled HIV infection. We also enrolled unvaccinated participants previously infected with SARS-CoV-2. This group consisted of 34 PLWH and 28 HIV-uninfected individuals. 10 of the 34 (29%) SARS-CoV-2 infected only PLWH had detectable HIV viremia. We used records of a positive SARS-CoV-2 qPCR result, or when a positive result was absent, testing for SARS-CoV-2 nucleocapsid antibodies, to determine which vaccinated participants were SARS-CoV-2 infected prior to vaccination. Neutralization capacity was assessed using participant plasma in a live virus neutralization assay of the Delta SARS-CoV-2 variant currently dominating infections in South Africa. This study was approved by the Biomedical Research Ethics Committee at the University of KwaZulu-Natal (reference BREC/00001275/2020). FindingsThe majority (68%) of Ad26.CoV2.S vaccinated HCW were found to be previously infected with SARS-CoV-2. In this group, Delta variant neutralization was 9-fold higher compared to the infected only group (GMT=306 versus 36, p<0.0001) and 26-fold higher relative to the vaccinated only group (GMT=12, p<0.0001). No significant difference in Delta variant neutralization capacity was observed in vaccinated and previously SARS-CoV-2 infected PLWH relative to vaccinated and previously SARS-CoV-2 infected, HIV-uninfected participants (GMT=307 for HIV-uninfected, 300 for PLWH, p=0.95). SARS-CoV-2 infected, unvaccinated PLWH showed 7-fold reduced neutralization of the Delta variant relative to HIV-uninfected participants (GMT=105 for HIV-uninfected, 15 for PLWH, p=0.001). There was a higher frequency of non-responders in PLWH relative to HIV-uninfected participants in the SARS-CoV-2 infected unvaccinated group (27% versus 0%, p=0.0029) and 60% of HIV viremic versus 13% of HIV suppressed PLWH were non-responders (p=0.0088). In contrast, the frequency of non-responders was low in the vaccinated/infected group, and similar between HIV-uninfected and PLWH. Vaccinated only participants showed a low neutralization of the Delta variant, with a stronger response in PLWH (GMT=6 for HIV-uninfected, 73 for PLWH, p=0.02). InterpretationThe neutralization response of the Delta variant following Ad26.CoV2.S vaccination in PLWH with well controlled HIV was not inferior to HIV-uninfected study participants. In SARS-CoV-2 infected and non-vaccinated participants, the presence of HIV infection reduced the neutralization response to SARS-CoV-2 infection, and this effect was strongest in PLWH with detectable HIV viremia FundingSouth African Medical Research Council, The Bill & Melinda Gates Foundation.

Prior infection with SARS-CoV-2 boosts and broadens Ad26.COV2.S immunogenicity in a variant dependent manner

The Johnson and Johnson Ad26.COV2.S single dose vaccine represents an attractive option for COVID-19 vaccination in resource limited countries. We examined the effect of prior infection with different SARS-CoV-2 variants on Ad26.COV2.S immunogenicity. We compared participants who were SARS-CoV-2 naive with those either infected with the ancestral D614G virus, or infected in the second wave when Beta predominated. Prior infection significantly boosted spike binding antibodies, antibody-dependent cellular cytotoxicity and neutralizing antibodies against D614G, Beta and Delta, however neutralization cross-reactivity varied by wave. Robust CD4 and CD8 T cell responses were induced after vaccination, regardless of prior infection. T cell recognition of variants was largely preserved, apart from some reduction in CD8 recognition of Delta. Thus, Ad26.COV2.S vaccination following infection may result in enhanced protection against COVID-19. The impact of the infecting variant on neutralization breadth after vaccination has implications for the design of second-generation vaccines based on variants of concern.

Neutralizing antibodies elicited by the Ad26.COV2.S COVID-19 vaccine show reduced activity against 501Y.V2 (B.1.351), despite protection against severe disease by this variant.

The emergence of SARS-CoV-2 variants, such as 501Y.V2, with immune evasion mutations in the spike has resulted in reduced efficacy of several COVID-19 vaccines. However, the efficacy of the Ad26.COV2.S vaccine, when tested in South Africa after the emergence of 501Y.V2, was not adversely impacted. We therefore assessed the binding and neutralization capacity of n=120 South African sera (from Day 29, post-vaccination) from the Janssen phase 3 study, Ensemble. Spike binding assays using both the Wuhan-1 D614G and 501Y.V2 Spikes showed high levels of cross-reactivity. In contrast, in a subset of 27 sera, we observed significantly reduced neutralization of 501Y.V2 compared to Wuhan-1 D614G, with 22/27 (82%) of sera showing no detectable neutralization of 501Y.V2 at Day 29. These data suggest that even low levels of neutralizing antibodies may contribute to protection from moderate/severe disease. In addition, Fc effector function and T cells may play an important role in protection by this vaccine against 501Y.V2.