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Join us on May 26 for our next webinar!

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Understanding memory B cell responses induced by heterologous SARS-CoV-2 exposure

Thursday May 26, 2022 11am ET / 5pm CET

Speaker: Laura M. Walker, PhD

Senior Director of Antibody Sciences at Adimab and Chief Scientific Officer and a co-founder of Adagio Therapeutics.

Understanding immune responses following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) breakthrough infection will facilitate the development of next-generation vaccines. Towards this end, Dr. Walker and her colleagues profiled spike (S)-specific B cell responses following Omicron/BA.1 infection in mRNA-vaccinated donors. The acute antibody response was characterized by high levels of somatic hypermutation and a bias toward recognition of ancestral SARS-CoV-2 strains, suggesting the early activation of vaccine-induced memory B cells. BA.1 breakthrough infection induced a shift in B cell immunodominance hierarchy from the S2 subunit toward the receptor binding domain (RBD). A large proportion of RBD-directed neutralizing antibodies isolated from BA.1 breakthrough infection donors displayed convergent sequence features and broadly recognized SARS-CoV-2 variants of concern. Dr. Walker will discuss these findings, which provide insights into the role of pre-existing immunity in shaping the B cell response to heterologous SARS-CoV-2 variant exposure.

Registration is open!

Untangling Pandemics in a Data-Driven World. The Evolution of SARS-CoV-2

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Antibody Engineering & Therapeutics, held in December 2021, offered many opportunities to hear exciting and informative presentations by experts in the field. We are pleased to present here a summary of a plenary lecture by Prof. Kristian Andersen (Scripps Research Institute), kindly written by Dr. Czeslaw Radziejewski.

 

Untangling Pandemics in a Data-Driven World. The Evolution of SARS-CoV-2.
Kristian Andersen, Professor of Immunology and Microbiology, Scripps Research Institute

Professor Andersen’s lab conducts genomic epidemiology of different viruses using miniaturized PCR testing and large-scale genomic sequencing. Previously, his lab studied Lassa, West Nile, Ebola, and Zika viruses, and now the lab is examining SARS-CoV-2. The goal of the research to understand the emergence of new viruses and their local transmission,[1] as well as the evolution and spread of these viruses. In order to understand connectedness of the sequences, samples of virus are taken from the infected populations, then viruses are sequenced and analyzed.

SARS-CoV-2 was first detected in December 2019 in people who frequented the Wuhan Huanan market in Guangdong province, China. Based on large-scale sequencing, it was possible to estimate that the epidemic started in November 2019. SARS-CoV-2 is remarkably similar to SARS-CoV-1 in terms of the receptor in humans (ACE2), the animal reservoir (bats), and the fact that both are associated with wet markets.[2] The number of introductions in humans is at present unknown and any intermediate hosts are still also unknown. For SARS-Cov-1 the intermediate hosts were civets and raccoon dogs. Curiously, both viruses were introduced into humans in the month of November, SARS-Cov-1 in 2002, SARS-Cov-2 in 2019. Since 2002, trade and farming of wild animals have decreased in China, so the risk of multiple spillover was reduced. A farm in Hubei was previously found to have animals infected with SARS-CoV-1. Viral sequences determined in animals were very similar to those found in humans infected with SARS-Cov-1. The same farm recently had civets infected with SARS-CoV-2.

Since 1965, nine different coronaviruses have emerged in human population. Coronaviruses are part of Sarbecoviruses, which are widespread in Southeast Asia. Horseshoe bats are also widespread in that region and they are a reservoir of Sarbecoviruses. SARS-CoV-2 spreads easily and, unlike a seasonal influenza, it can infect both upper and lower parts of the respiratory system as well as other organs. High infectivity of many variants of CoV-2 can be attributed to the presence of the receptor binding domain (RBD) and also the presence of a polybasic cleavage site that allows the spike protein to be processed into two subunits and facilitates fast and widespread infection. The SARS-CoV-2 RBD is similar to the RBD of other viruses that infect animals such as bats and pangolins. SARS CoV-2 shows a very high rate of evolution, which in the past two years has resulted in multiple variants.[3] New variants have rapidly displaced the old ones. Omicron, which presumably emerged as a result of immune escape, has an extremely mutated lineage. For example, it has 40 mutations in the spike protein compared to original virus, most of which appears on the outside RBD of the spike protein. The mutations may lead to further optimization of binding to AC2, but also potentially usage of a coreceptor is involved. The spread of omicron is much faster than other variants. This variant is cable of causing new infection and reinfection. Almost entire the human population is susceptible to omicron infection, and SARS-CoV-2 now appears to be endemic.

In summary, SARS-Cov-2 is a fast-evolving virus and several factors such as evolutionary rate, mutational supply, mutational tolerance will determine its further evolution. However, we now have tools to fight the pandemics, including vaccines, anti-viral drugs, rapid tests, masks and better understanding of the virus.

1. Zeller et al. Emergence of an Early SARS-CoV-2 Epidemic in the United States. Cell 184(19):4939-4952, 2021. DOI: 10.1016/j.cell.2021.07.030.

2. Holmes et al. The Origins of SARS-CoV-2: A Critical Review. Cell 184(19):4848-4856, 2021. DOI: 10.1016/j.cell.2021.08.017.

3. Washington et al. Emergence and Rapid Transmission of SARS-CoV-2 B.1.1.7 in the United States. Cell 184(10):2587-2594, 2021. DOI: 10.1016/j.cell.2021.03.052.

FDA issues emergency use authorization for bebtelovimab

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On February 11, 2022, the U.S. Food and Drug Administration (FDA) has issued an Emergency Use Authorization (EUA) for bebtelovimab (LY-CoV1404), an anti-SARS-CoV-2 monoclonal antibody that demonstrates neutralization against the Omicron variant. Bebtelovimab targets the SARS-CoV-2 spike glycoprotein receptor binding domain. The EUA was issued to Eli Lilly and Co.

The EUA for bebtelovimab is supported by clinical and nonclinical data. The clinical data are from a Phase 2, randomized, single-dose clinical trial (NCT04634409) evaluating the efficacy of bebtelovimab alone and bebtelovimab combined with other monoclonal antibodies for treating mild to moderate COVID-19.

Bebtelovimab is authorized for the treatment of mild-to-moderate COVID-19 in adults and pediatric patients (12 years of age and older weighing at least 40 kg) with positive results of direct SARS-CoV-2 viral testing, and who are at high risk for progression to severe COVID-19, including hospitalization or death, and for whom alternative COVID-19 treatment options approved or authorized by FDA are not accessible or clinically appropriate. The authorized dose of bebtelovimab is 175 mg given as an intravenous injection over at least 30 seconds. A fact sheet for health care providers with additional information about bebtelovimab can be found here.

As previously announced, Lilly signed an agreement with the U.S. government to supply up to 600,000 doses of investigational drug bebtelovimab for at least $720 million.

Xevudy (sotrovimab) approved in the EU for COVID-19

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On December 17, 2021, GlaxoSmithKline plc and Vir Biotechnology, Inc. announced that the European Commission has granted a marketing authorization to Xevudy (sotrovimab) for the early treatment of COVID-19. Sotrovimab is now approved in the European Union for the treatment of adults and adolescents (aged 12 years and over and weighing at least 40kg) with COVID-19 who do not require supplemental oxygen and who are at increased risk of progressing to severe COVID-19. Sotrovimab, a human anti-SARS-CoV-2 IgG1 antibody derived from the B cell of a COVID-19 survivor, was engineered to achieve high concentration in the lungs and to have an extended half-life.

The marketing application included data from the randomized, double-blind, placebo-controlled Phase 1/2/3 COMET-ICE trial (NCT04545060), which evaluated the effects of sotrovimab in non-hospitalized adults with mild-to-moderate COVID-19 symptoms and a positive SARS-CoV-2 test result. Patients received a single intravenous dose of 500 mg sotrovimab or placebo. Study results showed that treatment with sotrovimab resulted in a 79% reduction in all-cause hospitalizations for more than 24 hours or death due to any cause by Day 29 compared to placebo, meeting the primary endpoint of the trial. In total, 30 (6%) of the 529 patients in the placebo arm progressed, compared to six (1%) of the 528 patients receiving sotrovimab.

Sotrovimab is authorized for emergency use in the US, conditional or provisional marketing authorizations in Great Britain, Australia, and Saudi Arabia, as well as temporary authorizations in other countries. Sotrovimab is administered as a 500-milligram single IV dose given over 30 minutes by health care providers. The product has, however, also been formulated for IM administration. In the randomized, open-label COMET-TAIL Phase 3 trial, which achieved its primary endpoint, IM administration of sotrovimab was non-inferior to IV administration for the early treatment of mild-to-moderate COVID-19 in high-risk, non-hospitalized adults and adolescents (12 years of age and older).

FDA grants emergency use authorization to anti-SARS-COV-2 mAb Evusheld

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On December 8, 2021, the U.S. Food and Drug Administration issued an emergency use authorization (EUA) for AstraZeneca’s Evusheld (tixagevimab co-packaged with cilgavimab and administered together) for the pre-exposure prophylaxis (prevention) of COVID-19 in certain adults and pediatric individuals (12 years of age and older weighing at least 40 kilograms [about 88 pounds]).

Evusheld, comprising the combination of 2 human anti-SARS-CoV-2 IgG1k antibodies, was derived from B cells from convalescent patients after infection with SARS-CoV-2. Discovered by Vanderbilt University Medical Center, the antibodies bind to distinct sites on the SARS-CoV-2 spike protein. These antibodies were licensed to AstraZeneca in June 2020, and then engineered with mutations that extend half-life (YTE) and reduce Fc receptor and complement C1q binding (L234F, L235E, P331S). The primary data supporting the EUA came from the PROVENT clinical study, which is assessing the safety and efficacy of a single 300 mg dose of AZD7442 compared to placebo for the prevention of COVID-19. At the primary analysis, the study data showed AZD7442 reduced the risk of developing symptomatic COVID-19 by 77% (95% CI: 46, 90), compared to placebo.

Evusheld is the 4th anti-SARS-CoV-2 antibody product granted an EUA. See our COVID-19 Biologics Tracker for information about other anti-SARS-CoV-2 antibodies.