Novavax NVX-COV2373 triggers potent neutralization of Omicron sub-lineages

The SARS-CoV-2 Omicron (B.1.1.529) Variant of Concern (VOC) and its sub-lineages (including BA.2, BA.4/5, BA.2.12.1) contain spike mutations that confer high level resistance to neutralizing antibodies. The NVX-CoV2373 vaccine, a protein nanoparticle vaccine, has value in countries with constrained cold-chain requirements. Here we report neutralizing titers following two or three doses of NVX-CoV2373. We show that after two doses, Omicron sub-lineages BA.1 and BA.4 were resistant to neutralization by 72% (21/29) and 59% (17/29) of samples. However, after a third dose of NVX-CoV2373, we observed high titers against Omicron BA.1 (GMT: 1,197) and BA.4 (GMT: 582), with responses similar in magnitude to those triggered by three doses of an mRNA vaccine. These data are of particular relevance as BA.4 is emerging to become the dominant strain in many locations, and highlight the potential utility of the NVX-CoV2373 vaccine as a booster in resource-limited environments.

SARS-CoV-2 spike T cell responses induced upon vaccination or infection remain robust against Omicron

The SARS-CoV-2 Omicron variant has multiple Spike (S) protein mutations that contribute to escape from the neutralizing antibody responses, and reducing vaccine protection from infection. The extent to which other components of the adaptive response such as T cells may still target Omicron and contribute to protection from severe outcomes is unknown. We assessed the ability of T cells to react with Omicron spike in participants who were vaccinated with Ad26.CoV2.S or BNT162b2, and in unvaccinated convalescent COVID-19 patients (n = 70). We found that 70-80% of the CD4 and CD8 T cell response to spike was maintained across study groups. Moreover, the magnitude of Omicron cross-reactive T cells was similar to that of the Beta and Delta variants, despite Omicron harbouring considerably more mutations. Additionally, in Omicron-infected hospitalized patients (n = 19), there were comparable T cell responses to ancestral spike, nucleocapsid and membrane proteins to those found in patients hospitalized in previous waves dominated by the ancestral, Beta or Delta variants (n = 49). These results demonstrate that despite Omicrons extensive mutations and reduced susceptibility to neutralizing antibodies, the majority of T cell response, induced by vaccination or natural infection, cross-recognises the variant. Well-preserved T cell immunity to Omicron is likely to contribute to protection from severe COVID-19, supporting early clinical observations from South Africa.

Breakthrough Covid-19 infections during periods of circulating Beta, Delta and Omicron variants of concern, among health care workers in the Sisonke Ad26.COV2.S vaccine trial, South Africa

BackgroundWe report breakthrough infections (BTIs) during periods of circulating Beta, Delta and Omicron variants of concern, among health care workers (HCW) participating in the Sisonke phase 3B Ad26.COV2.S vaccine trial (ClinicalTrials.gov number, NCT04838795). Data were gathered between 17 February and 15 December 2021. Duration of each period in this study was 89 days for Beta, 180 days or Delta and 30 days for Omicron. ResultsA total of 40 538 BTIs were observed, with 609 during Beta, 22 279 during Delta and 17 650 during Omicron. By 15 December, daily infections during Omicron were three times that seen during the peak observed during Delta. However, unlike the Delta period, with Omicron there was a clear and early de-coupling of hospitalisation from cases as a percentage of the Delta peak curves. Omicron significantly infected a greater proportion of HCW in the 18-30 year age-group, compared with the 55+ age group. There were 1 914 BTI-related hospitalisations - 77, 1 429 and 408 in the Beta (89 days), Delta (180 days) and Omicron (30 days) periods, respectively. During Omicron, 91% hospitalized HCWs required general ward care, 6% high care and 3% intensive care, compared with 89% general ward care, 4% high care and 7% intensive care, during Delta and 78% general care, 7% high care and 16% intensive care during Beta (p<0.001). During Beta and Beta 43% of hospitalized HCW needed supplementary oxygen and 7-8% needed ventilation, compared with 16% and 0.2% respectively during the Omicron period (p<0.001). Median length of hospitalization was significantly lower with Omicron compared with Beta and Delta (3 days compared with 5-6 days, p<0.001). ConclusionsWe illustrate more BTIs but reassuringly less severe Covid-19 with Omicron. Re-infections and Omicron-driven primary infections were likely driven by high population SARS-CoV-2 seroprevalence, waning vaccine effectiveness over time, increased Omicron infectivity, Omicron immune evasion or a combination of these and need further investigation. Follow-up of this cohort will continue and reports will be updated, as time and infections accrue.

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.

The continuous evolution of SARS-CoV-2 in South Africa: a new lineage with rapid accumulation of mutations of concern and global detection

Global genomic surveillance of SARS-CoV-2 has identified variants associated with increased transmissibility, neutralization resistance and disease severity. Here we report the emergence of the PANGO lineage C.1.2, detected at low prevalence in South Africa and eleven other countries. The emergence of C.1.2, associated with a high substitution rate, includes changes within the spike protein that have been associated with increased transmissibility or reduced neutralization sensitivity in SARS-CoV-2 VOC/VOIs. Like Beta and Delta, C.1.2 shows significantly reduced neutralization sensitivity to plasma from vaccinees and individuals infected with the ancestral D614G virus. In contrast, convalescent donors infected with either Beta or Delta showed high plasma neutralization against C.1.2. These functional data suggest that vaccine efficacy against C.1.2 will be equivalent to Beta and Delta, and that prior infection with either Beta or Delta will likely offer protection against C.1.2.

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.