Immune Correlates Analysis of a Single Ad26.COV2.S Dose in the ENSEMBLE COVID-19 Vaccine Efficacy Clinical Trial

Fong, Youyi; McDermott, Adrian B.; Benkeser, David; Roels, Sanne; Stieh, Daniel J.; Vandebosch, An; Gars, Mathieu Le; Roey, Griet A. Van; Houchens, Christopher R.; Martins, Karen; Jayashankar, Laksmi; Castellino, Flora; Amoa-Awua, Obrimpong; Basappa, Manjula; Flach, Britta; Lin, Bob C.; Moore, Christopher; Naisan, Mursal; Naqvi, Muhammed; Narpala, Sandeep; O’Connell, Sarah; Mueller, Allen; Serebryannyy, Leo; Castro, Mike; Wang, Jennifer; Petropoulos, Christos J.; Luedtke, Alex; Hyrien, Ollivier; Lu, Yiwen; Yu, Chenchen; Borate, Bhavesh; Laan, Lars W. P. van der; Hejazi, Nima S.; Kenny, Avi; Carone, Marco; Wolfe, Daniel; Sadoff, Jerald C.; Gray, Glenda; Grinsztejn, Beatriz; Goepfert, Paul; Sousa, Leonardo Paiva de; Maboa, Rebone; Randhawa, April; Andrasik, Michele P.; Hendriks, Jenny; Truyers, Carla; Struyf, Frank; Schuitemaker, Hanneke; Douoguih, Macaya; Kublin, James G.; Corey, Lawrence; Neuzil, Kathleen M.; Carpp, Lindsay N.; Follmann, Dean; Gilbert, Peter B.; Koup, Richard A.; Donis, Ruben O.

doi:10.1101/2022.04.06.22272763

Cited by 16 publications

(33 citation statements)

References 37 publications

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“…Error bars represent 95% CIs. vaccine studies helped provide evidence for establishing a neutralizing antibody surrogate endpoint for COVID-19 vaccines [23][24][25][26] with applications including a noninferiority, neutralization-based endpoint approach to support vaccine emergency use authorization or approval 27,28 . Moreover, our findings 23 are informing policy decisions (for example, on boosters) and will potentially aid design of future trials, including those of pan-coronavirus vaccines.…”

Section: Fig 5 | Pt 80 Values To Autologous Acquired Viruses At Hiv-1...mentioning

confidence: 99%

Neutralization titer biomarker for antibody-mediated prevention of HIV-1 acquisition

Gilbert

Huang

deCamp

et al. 2022

Nat Med

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The Antibody Mediated Prevention trials showed that the broadly neutralizing antibody (bnAb) VRC01 prevented acquisition of human immunodeficiency virus-1 (HIV-1) sensitive to VRC01. Using AMP trial data, here we show that the predicted serum neutralization 80% inhibitory dilution titer (PT80) biomarker—which quantifies the neutralization potency of antibodies in an individual’s serum against an HIV-1 isolate—can be used to predict HIV-1 prevention efficacy. Similar to the results of nonhuman primate studies, an average PT80 of 200 (meaning a bnAb concentration 200-fold higher than that required to reduce infection by 80% in vitro) against a population of probable exposing viruses was estimated to be required for 90% prevention efficacy against acquisition of these viruses. Based on this result, we suggest that the goal of sustained PT80 <200 against 90% of circulating viruses can be achieved by promising bnAb regimens engineered for long half-lives. We propose the PT80 biomarker as a surrogate endpoint for evaluatinon of bnAb regimens, and as a tool for benchmarking candidate bnAb-inducing vaccines.

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Section: Fig 5 | Pt 80 Values To Autologous Acquired Viruses At Hiv-1...mentioning

confidence: 99%

Neutralization titer biomarker for antibody-mediated prevention of HIV-1 acquisition

Gilbert

Huang

deCamp

et al. 2022

Nat Med

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“…In this comparison for ENSEMBLE we restricted to data from the U.S. study sites (ENSEMBLE-US) in order to match the fact that the correlates analyses of PREVENT-19 and COVE both restricted to the U.S. Direct comparison of correlates of risk and vaccine efficacy at a given spike IgG concentration values across the four trials is possible because the Meso Scale Discovery (MSD) assay at Nexelis that was used in PREVENT-19, the MSD assay at VRC that was used in COVE 25 and ENSEMBLE, 26 and the MSD assay at PPD that was used in COV002, 27 all had the original assay readout (in Arbitrary Units/ml) transformed to WHO International Standard 20/136 international units (BAU/ml scale). 32, 33 Direct comparison of correlates of risk and vaccine efficacy at a given nAb ID50 titer in PREVENT-19 to results at the same nAb ID50 titer in COVE is possible because the Duke assay (used in COVE) and the Monogram assay (used in PREVENT-19) underwent concordance testing 25, 34 and were calibrated to the WHO IS 20/136 (described in refs.…”

Section: Resultsmentioning

confidence: 99%

“…The second correlates analysis in this program evaluated the Ad26.COV2.S COVID-19 vaccine in the international ENSEMBLE phase 3 trial, studying the same antibody markers as correlates, and showed that nAb ID50 measured four weeks after a single vaccine dose was associated with single-dose vaccine efficacy against symptomatic COVID-19, and spike IgG and RBD IgG showed non-significant trends toward associating with vaccine efficacy against symptomatic COVID-19. 26 External to the USG-supported program, the phase 3 trial of the AZD12222 (ChAdOx1 nCoV-19) vaccine in the United Kingdom showed that the same three markers, measured 4 weeks post second vaccination, all associated with vaccine efficacy against symptomatic COVID-19. 27 In the current article, we present the correlates analysis for the PREVENT-19 study.…”

Section: Introductionmentioning

confidence: 99%

Immune Correlates Analysis of the PREVENT-19 COVID-19 Vaccine Efficacy Clinical Trial

Fong

Huang

Benkeser

et al. 2022

Preprint

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In the randomized, placebo-controlled PREVENT-19 phase 3 trial conducted in the U.S. and Mexico of the NVX-CoV2373 adjuvanted, recombinant spike protein nanoparticle vaccine, anti-spike binding IgG concentration (spike IgG) and pseudovirus 50% neutralizing antibody titer (nAb ID50) measured two weeks after two doses were assessed as correlates of risk and as correlates of protection against PCR-confirmed symptomatic SARS-CoV-2 infection (COVID-19). These immune correlates analyses were conducted in the U.S. cohort of baseline SARS-CoV-2 negative per-protocol participants using a case-cohort design that measured the antibody markers from all 12 vaccine recipient breakthrough COVID-19 cases starting 7 days post antibody measurement and from 639 vaccine recipient non-cases (Mexico was excluded due to zero breakthrough cases with the efficacy data cut-off date April 19, 2021). In vaccine recipients, the baseline risk factor-adjusted hazard ratio of COVID-19 was 0.36 (95% CI: 0.20, 0.63), p<0.001 (adjusted p-0.005) per 10-fold increase in IgG spike concentration and 0.39 (0.19, 0.82), p=0.013 (adjusted p=0.030) per 10-fold increase in nAb ID50 titer. At spike IgG concentration 100, 1000, and 6934 binding antibody units/ml (100 is the 3rd percentile, 6934 is the 97.5th percentile), vaccine efficacy to reduce the probability of acquiring COVID-19 at 59 days post marker measurement was 65.5% (95% CI: 23.0%, 90.8%), 87.7% (77.7%, 94.4%), and 94.8% (88.0%, 97.9%), respectively. At nAb ID50 titers of 50, 100, 1000, and 7230 IU50/ml (50 is the 5th percentile, 7230 the 97.5th percentile), these estimates were 75.7% (49.8%, 93.2%), 81.7% (66.3%, 93.2%), 92.8% (85.1%, 97.4%) and 96.8% (88.3%, 99.3%). The same two antibody markers were assessed as immune correlates via the same study design and statistical analysis in the mRNA-1273 phase 3 COVE trial (except in COVE the markers were measured four weeks post dose two). Spike IgG levels were slightly lower and nAb ID50 titers slightly higher after NVX-CoV2373 than after mRNA-1273 vaccination. The strength of the nAb ID50 correlate was similar between the trials, whereas the spike IgG antibodies appeared to correlate more strongly with NVX-CoV2373 in PREVENT-19, as quantified by the hazard ratio and the degree of change in vaccine efficacy across antibody levels. However, the relatively few breakthrough cases in PREVENT-19 limited the ability to infer a stronger correlate. The conclusion is that both markers were consistent correlates of protection for the two vaccines, supporting potential cross-vaccine platform applications of these markers for guiding decisions about vaccine approval and use.

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Section: Discussionmentioning

confidence: 99%

“…Booster vaccination further enhanced the cross-neutralising activities and the proportion of plasma samples with detectable neutralizing antibodies in these individuals with breakthrough Delta variant infection 6 months earlier [18]. Because neutralising antibodies titers are well correlated with protection [24, 25], the data suggest that booster vaccination could still be beneficial to individuals with breakthrough infection in protecting against Omicron variant [21, 23]. Likewise, the decline in neutralsing antibody levels to sublineages BA.1 and BA.2 at week 15 after the first booster dose suggest that a second booster doses might be needed to maintain the long-term protection of vaccine against Omicron variant [12].…”

Section: Discussionmentioning

confidence: 99%

Kinetics of neutralising antibodies against Omicron variant in Vietnamese healthcare workers after primary immunisation with ChAdOx1-S and booster with BNT162b2

Châu

Nguyet

Dung

et al. 2022

Preprint

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We studied the development and persistence of neutralising antibodies against SARS-CoV-2 ancestral strain, and Delta and Omicron (BA.1 and BA.2) variants in Vietnamese healthcare workers (HCWs) up to 15 weeks after booster vaccination. We included 47 HCWs with different pre-existing immune statuses (group 1 (G1): n=21, and group 2 (G2): n=26 without and with prior breakthrough Delta variant infection, respectively). The study participants had completed primary immunisation with ChAdOx1-S and booster vaccination with BNT162b2. Neutralising antibodies were measured using a surrogate virus neutralisation assay. Of the 21 study participants in G1, neutralising antibodies against ancestral strain, Delta variant, BA.1 and BA.2 were (almost) abolished at month 8 after the second dose, but all had detectable neutralising antibodies to the study viruses at week two post booster dose. Of the 26 study participants in G2, neutralising antibody levels to BA.1 and BA.2 were significantly higher than those to the corresponding viruses measured at week 2 post breakthrough infection and before the booster dose. At week 15 post booster vaccination, neutralising antibodies to BA.1 and BA.2 dropped significantly, with more profound changes observed in those without breakthrough Delta variant infection. Booster vaccination enhanced neutralising activities against ancestral strain and Delta variant, as compared to those induced by primary vaccination. These responses were maintained at high levels for at least 15 weeks. Our findings emphasise the importance of the first booster dose in producing cross-neutralising antibodies against Omicron variant. A second booster dose might be needed to maintain long-term protection against Omicron variant.

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Immune Correlates Analysis of a Single Ad26.COV2.S Dose in the ENSEMBLE COVID-19 Vaccine Efficacy Clinical Trial

Cited by 16 publications

References 37 publications

Neutralization titer biomarker for antibody-mediated prevention of HIV-1 acquisition

Neutralization titer biomarker for antibody-mediated prevention of HIV-1 acquisition

Immune Correlates Analysis of the PREVENT-19 COVID-19 Vaccine Efficacy Clinical Trial

Kinetics of neutralising antibodies against Omicron variant in Vietnamese healthcare workers after primary immunisation with ChAdOx1-S and booster with BNT162b2

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