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High-titer neutralization of Mu and C.1.2 SARS-CoV-2 variants by vaccine-elicited antibodies of previously infected individuals

Tada, Takuya; Zhou, Hao; Dcosta, Belinda M; Samanovic, Marie I; Cornelius, Amber; Herati, Ramin S; Mulligan, Mark J; Landau, Nathaniel R
Recently identified severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants Mu and C.1.2 have spike proteins with mutations that may confer resistance to natural and vaccine-elicited antibodies. Analysis of neutralizing antibody titers in the sera of vaccinated individuals without previous history of infection and from convalescent individuals show partial resistance of the viruses. In contrast, sera from individuals with a previous history of SARS-CoV-2 infection who were subsequently vaccinated neutralize variants with titers 4- to 11-fold higher, providing a rationale for vaccination of individuals with previous infection. The heavily mutated C.1.2 spike is the most antibody neutralization-resistant spike to date; however, the avidity of C.1.2 spike protein for angiotensin-converting enzyme 2 (ACE2) is low. This finding suggests that the virus evolved to escape the humoral response but has a decrease in fitness, suggesting that it may cause milder disease or be less transmissible. It may be difficult for the spike protein to evolve to escape neutralizing antibodies while maintaining high affinity for ACE2.
PMID: 34982967
ISSN: 2211-1247
CID: 5107032

Phase 3 Safety and Efficacy of AZD1222 (ChAdOx1 nCoV-19) Covid-19 Vaccine

Falsey, Ann R; Sobieszczyk, Magdalena E; Hirsch, Ian; Sproule, Stephanie; Robb, Merlin L; Corey, Lawrence; Neuzil, Kathleen M; Hahn, William; Hunt, Julie; Mulligan, Mark J; McEvoy, Charlene; DeJesus, Edwin; Hassman, Michael; Little, Susan J; Pahud, Barbara A; Durbin, Anna; Pickrell, Paul; Daar, Eric S; Bush, Larry; Solis, Joel; Carr, Quito Osuna; Oyedele, Temitope; Buchbinder, Susan; Cowden, Jessica; Vargas, Sergio L; Benavides, Alfredo Guerreros; Call, Robert; Keefer, Michael C; Kirkpatrick, Beth D; Pullman, John; Tong, Tina; Isaacs, Margaret Brewinski; Benkeser, David; Janes, Holly E; Nason, Martha C; Green, Justin A; Kelly, Elizabeth J; Maaske, Jill; Mueller, Nancy; Shoemaker, Kathryn; Takas, Therese; Marshall, Richard P; Pangalos, Menelas N; Villafana, Tonya; Gonzalez-Lopez, Antonio; [Eckhardt, Benjamin]
BACKGROUND:The safety and efficacy of the AZD1222 (ChAdOx1 nCoV-19) vaccine in a large, diverse population at increased risk for severe acute respiratory syndrome coronavirus 2Â (SARS-CoV-2) infection in the United States, Chile, and Peru has not been known. METHODS:In this ongoing, double-blind, randomized, placebo-controlled, phase 3 clinical trial, we investigated the safety, vaccine efficacy, and immunogenicity of two doses of AZD1222 as compared with placebo in preventing the onset of symptomatic and severe coronavirus disease 2019 (Covid-19) 15 days or more after the second dose in adults, including older adults, in the United States, Chile, and Peru. RESULTS:A total of 32,451 participants underwent randomization, in a 2:1 ratio, to receive AZD1222 (21,635 participants) or placebo (10,816 participants). AZD1222 was safe, with low incidences of serious and medically attended adverse events and adverse events of special interest; the incidences were similar to those observed in the placebo group. Solicited local and systemic reactions were generally mild or moderate in both groups. Overall estimated vaccine efficacy was 74.0% (95% confidence interval [CI], 65.3 to 80.5; P<0.001) and estimated vaccine efficacy was 83.5% (95% CI, 54.2 to 94.1) in participants 65 years of age or older. High vaccine efficacy was consistent across a range of demographic subgroups. In the fully vaccinated analysis subgroup, no severe or critical symptomatic Covid-19 cases were observed among the 17,662 participants in the AZD1222 group; 8 cases were noted among the 8550 participants in the placebo group (<0.1%). The estimated vaccine efficacy for preventing SARS-CoV-2 infection (nucleocapsid antibody seroconversion) was 64.3% (95% CI, 56.1 to 71.0; P<0.001). SARS-CoV-2 spike protein binding and neutralizing antibodies increased after the first dose and increased further when measured 28 days after the second dose. CONCLUSIONS:AZD1222 was safe and efficacious in preventing symptomatic and severe Covid-19 across diverse populations that included older adults. (Funded by AstraZeneca and others; number, NCT04516746.).
PMID: 34587382
ISSN: 1533-4406
CID: 5027212

Robust immune responses are observed after one dose of BNT162b2 mRNA vaccine dose in SARS-CoV-2 experienced individuals

Samanovic, Marie I; Cornelius, Amber R; Gray-Gaillard, Sophie L; Allen, Joseph Richard; Karmacharya, Trishala; Wilson, Jimmy P; Wesley Hyman, Sara; Tuen, Michael; Koralov, Sergei B; Mulligan, Mark J; Sedaghat Herati, Ramin
[Figure: see text].
PMID: 34874183
ISSN: 1946-6242
CID: 5086932

Knowledge and Attitudes Toward Covid-19 and Vaccines Among a New York Haredi-Orthodox Jewish Community

Carmody, Ellie R; Zander, Devon; Klein, Elizabeth J; Mulligan, Mark J; Caplan, Arthur L
The Covid-19 pandemic has exposed the difficulty of the US public health system to respond effectively to vulnerable subpopulations, causing disproportionate rates of morbidity and mortality. New York Haredi-Orthodox Jewish communities represent a group that have been heavily impacted by Covid-19. Little research has examined their experience or perceptions toward Covid-19 and vaccines. We conducted a cross-sectional, observational study to explore the experience of Covid-19 among Haredim. Paper surveys were self-administered between December 2020 and January 2021 in Haredi neighborhood pediatricians' offices in Brooklyn, New York. Of 102 respondents, 43% reported either a positive SARS-CoV-2 viral or antibody test. Participants trusted their physicians, Orthodox medical organizations, and rabbinic leaders for medical information. Knowledge of Covid-19 transmission and risk was good (69% answered ≥ 4/6 questions correctly). Only 12% of respondents would accept a Covid-19 vaccine, 41% were undecided and 47% were strongly hesitant. Independent predictors of strong vaccine hesitancy included believing natural infection to be better than vaccination for developing immunity (adjusted odds ratio [aOR] 4.28; 95% confidence interval [CI] 1.23-14.86), agreement that prior infection provides a path toward resuming communal life (aOR 4.10; 95% CI 1.22-13.77), and pandemic-related loss of trust in physicians (aOR 5.01; 95% CI 1.05-23.96). The primary disseminators of health information for self-protective religious communities should be stakeholders who understand these groups' unique health needs. In communities with significant Covid-19 experience, vaccination messaging may need to be tailored toward protecting infection-naïve individuals and boosting natural immunity against emerging variants.
PMID: 33999317
ISSN: 1573-3610
CID: 4876672

First-in-Human Study of Bamlanivimab in a Randomized Trial of Hospitalized Patients With COVID-19

Chen, Peter; Datta, Gourab; Grace Li, Ying; Chien, Jenny; Price, Karen; Chigutsa, Emmanuel; Brown-Augsburger, Patricia; Poorbaugh, Josh; Fill, Jeffrey; Benschop, Robert J; Rouphael, Nadine; Kay, Ariel; Mulligan, Mark J; Saxena, Amit; Fischer, William A; Dougan, Michael; Klekotka, Paul; Nirula, Ajay; Benson, Charles
Therapeutics for patients hospitalized with coronavirus disease 2019 (COVID-19) are urgently needed during the pandemic. Bamlanivimab is a potent neutralizing monoclonal antibody that blocks severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) attachment and entry into human cells, which could potentially lead to therapeutic benefit. J2W-MC-PYAA was a randomized, double-blind, sponsor unblinded, placebo-controlled, single ascending dose first-in-human trial (NCT04411628) in hospitalized patients with COVID-19. A total of 24 patients received either placebo or a single dose of bamlanivimab (700 mg, 2,800 mg, or 7,000 mg). The primary objective was assessment of safety and tolerability, including adverse events and serious adverse events, with secondary objectives of pharmacokinetic (PK) and pharmacodynamic analyses. Treatment-emergent adverse event (TEAE) rates were identical in the placebo and pooled bamlanivimab groups (66.7%). There were no apparent dose-related increases in the number or severity of TEAEs. There were no serious adverse events or deaths during the study, and no discontinuations due to adverse events. PKs of bamlanivimab is linear and exposure increased proportionally with dose following single i.v. administration. The half-life was ~ 17 days. These results demonstrate the favorable safety profile of bamlanivimab, and provided the initial critical evaluation of safety, tolerability, and PKs in support of the development of bamlanivimab in several ongoing clinical trials.
PMID: 34455583
ISSN: 1532-6535
CID: 5061122

Partial Resistance of SARS-CoV-2 Delta Variants to Vaccine-elicited Antibodies and Convalescent sera

Tada, Takuya; Zhou, Hao; Dcosta, Belinda M; Samanovic, Marie I; Mulligan, Mark J; Landau, Nathaniel R
Highly transmissible SARS-CoV-2 variants identified in India and designated B.1.617, Kappa (B.1.617.1), Delta (B.1.617.2), B.1.618 and B.1.36.29, contain spike mutations L452R, T478K, E484K, E484Q and N440K located within the spike receptor binding domain and thus could contribute to increased transmissibility and potentially allow re-infection or cause resistance to vaccine-elicited antibody. To address these issues, we used lentiviruses pseudotyped by variant spikes to measure their neutralization by convalescent sera, vaccine-elicited and Regeneron therapeutic antibodies and ACE2 affinity. Convalescent sera and vaccine-elicited antibodies neutralized viruses with Delta spike with 2-5-fold decrease in titer in different donors. Regeneron antibody cocktail neutralized virus with the Delta spike with a 2.6-fold decrease in titer. Neutralization resistance to serum antibodies and monoclonal antibodies was mediated by L452R mutation. These relatively modest decreases in antibody neutralization titer for viruses with variant spike proteins suggest that current vaccines will remain protective against the family of Delta variants.
PMID: 34723159
ISSN: 2589-0042
CID: 5037812

Heterologous SARS-CoV-2 Booster Vaccinations - Preliminary Report

Atmar, Robert L; Lyke, Kirsten E; Deming, Meagan E; Jackson, Lisa A; Branche, Angela R; El Sahly, Hana M; Rostad, Christina A; Martin, Judith M; Johnston, Christine; Rupp, Richard E; Mulligan, Mark J; Brady, Rebecca C; Frenck, Robert W; Bäcker, Martín; Kottkamp, Angelica C; Babu, Tara M; Rajakumar, Kumaravel; Edupuganti, Srilatha; Dobryzynski, David; Posavad, Christine M; Archer, Janet I; Crandon, Sonja; Nayak, Seema U; Szydlo, Daniel; Zemanek, Jillian; Islas, Clara P Dominguez; Brown, Elizabeth R; Suthar, Mehul S; McElrath, M Juliana; McDermott, Adrian B; O'Connell, Sarah E; Montefiori, David C; Eaton, Amanda; Neuzil, Kathleen M; Stephens, David S; Roberts, Paul C; Beigel, John H
Background/UNASSIGNED:While Coronavirus disease 2019 (Covid-19) vaccines are highly effective, breakthrough infections are occurring. Booster vaccinations have recently received emergency use authorization (EUA) for certain populations but are restricted to homologous mRNA vaccines. We evaluated homologous and heterologous booster vaccination in persons who had received an EUA Covid-19 vaccine regimen. Methods/UNASSIGNED:virus particles, or Pfizer-BioNTech BNT162b2 30-μg; nine combinations). The primary outcomes were safety, reactogenicity, and humoral immunogenicity on study days 15 and 29. Results/UNASSIGNED:458 individuals were enrolled: 154 received mRNA-1273, 150 received Ad26.CoV2.S, and 153 received BNT162b2 booster vaccines. Reactogenicity was similar to that reported for the primary series. Injection site pain, malaise, headache, and myalgia occurred in more than half the participants. Booster vaccines increased the neutralizing activity against a D614G pseudovirus (4.2-76-fold) and binding antibody titers (4.6-56-fold) for all combinations; homologous boost increased neutralizing antibody titers 4.2-20-fold whereas heterologous boost increased titers 6.2-76-fold. Day 15 neutralizing and binding antibody titers varied by 28.7-fold and 20.9-fold, respectively, across the nine prime-boost combinations. Conclusion/UNASSIGNED:Homologous and heterologous booster vaccinations were well-tolerated and immunogenic in adults who completed a primary Covid-19 vaccine regimen at least 12 weeks earlier. (Funded by National Institute of Allergy and Infectious Diseases; Clinical number, NCT04889209 ).
PMID: 34671773
ISSN: n/a
CID: 5086922

Methotrexate hampers immunogenicity to BNT162b2 mRNA COVID-19 vaccine in immune-mediated inflammatory disease

Haberman, Rebecca H; Herati, Ramin; Simon, David; Samanovic, Marie; Blank, Rebecca B; Tuen, Michael; Koralov, Sergei; Atreya, Raja; Tascilar, Koray; Allen, Joseph; Castillo, Rochelle; Cornelius, Amber; Rackoff, Paula; Solomon, Gary; Adhikari, Samrachana; Azar, Natalie; Rosenthal, Pamela; Izmirly, Peter; Samuels, Jonathan; Golden, Brian; Reddy, Soumya M; Neurath, Markus; Abramson, Steven B; Schett, Georg; Mulligan, Mark; Scher, Jose U
PMID: 34035003
ISSN: 1468-2060
CID: 4888812

Poor antigen-specific responses to the second BNT162b2 mRNA vaccine dose in SARS-CoV-2-experienced individuals

Samanovic, Marie I; Cornelius, Amber R; Wilson, Jimmy P; Karmacharya, Trishala; Gray-Gaillard, Sophie L; Allen, Joseph Richard; Hyman, Sara Wesley; Moritz, Gali; Ali, Mahnoor; Koralov, Sergei B; Mulligan, Mark J; Herati, Ramin Sedaghat
The advent of COVID-19 vaccines will play a major role in helping to end the pandemic that has killed millions worldwide. Vaccine candidates have demonstrated robust humoral responses and have protected against infection. However, efficacy trials were focused on individuals with no prior exposure to SARS-CoV-2, and, as a result, little is known about immune responses induced by these mRNA vaccines in individuals who recovered from COVID-19. Here, we evaluated immune responses in 32 subjects who received two-dose BNT162b2 mRNA vaccination. In individuals naive to SARS-CoV-2, we observed robust increases in humoral and antigen-specific antibody-secreting cell (ASC) responses following each dose of vaccine, whereas individuals with prior exposure to SARS-CoV-2 demonstrated strong humoral and antigen-specific ASC responses to the first dose but muted responses to the second dose of the vaccine for the time points studied. These data highlight an important gap in our knowledge and may have major implications for how these vaccines should be used to prevent COVID-19.
PMID: 33594383
ISSN: n/a
CID: 4786862

Discrete immune response signature to SARS-CoV-2 mRNA vaccination versus infection

Ivanova, Ellie N; Devlin, Joseph C; Buus, Terkild B; Koide, Akiko; Cornelius, Amber; Samanovic, Marie I; Herrera, Alberto; Zhang, Chenzhen; Desvignes, Ludovic; Odum, Niels; Ulrich, Robert; Mulligan, Mark J; Koide, Shohei; Ruggles, Kelly V; Herati, Ramin S; Koralov, Sergei B
Both SARS-CoV-2 infection and vaccination elicit potent immune responses. A number of studies have described immune responses to SARS-CoV-2 infection. However, beyond antibody production, immune responses to COVID-19 vaccines remain largely uncharacterized. Here, we performed multimodal single-cell sequencing on peripheral blood of patients with acute COVID-19 and healthy volunteers before and after receiving the SARS-CoV-2 BNT162b2 mRNA vaccine to compare the immune responses elicited by the virus and by this vaccine. Phenotypic and transcriptional profiling of immune cells, coupled with reconstruction of the B and T cell antigen receptor rearrangement of individual lymphocytes, enabled us to characterize and compare the host responses to the virus and to defined viral antigens. While both infection and vaccination induced robust innate and adaptive immune responses, our analysis revealed significant qualitative differences between the two types of immune challenges. In COVID-19 patients, immune responses were characterized by a highly augmented interferon response which was largely absent in vaccine recipients. Increased interferon signaling likely contributed to the observed dramatic upregulation of cytotoxic genes in the peripheral T cells and innate-like lymphocytes in patients but not in immunized subjects. Analysis of B and T cell receptor repertoires revealed that while the majority of clonal B and T cells in COVID-19 patients were effector cells, in vaccine recipients clonally expanded cells were primarily circulating memory cells. Importantly, the divergence in immune subsets engaged, the transcriptional differences in key immune populations, and the differences in maturation of adaptive immune cells revealed by our analysis have far-ranging implications for immunity to this novel pathogen.
PMID: 33907755
ISSN: n/a
CID: 4852132