AstraZeneca COVID-19 vaccine 76% effective in new analysis of U.S. trial

 AstraZeneca said its COVID-19 vaccine was 76% effective at preventing symptomatic illness in a new analysis of its major U.S. trial - a tad lower than the level announced earlier this week in a report that was criticised for using outdated information.

U.S. health officials had publicly rebuked the drugmaker for not using the most up-to-date information when it published an interim analysis on Monday that said the vaccine was 79% effective.

The latest data was based on 190 infections among more than 32,400 participants in the United States, Chile and Peru. The earlier interim data was based on 141 infections through Feb. 17.

“The primary analysis is consistent with our previously released interim analysis, and confirms that our COVID-19 vaccine is highly effective in adults,” Mene Pangalos, executive vice president of BioPharmaceuticals R&D at AstraZeneca said in a statement.

AstraZeneca said it plans to seek U.S. emergency use authorisation in the coming weeks and the latest data has been presented to the independent trial oversight committee, the Data Safety Monitoring Board.

AstraZeneca reiterated on Thursday that the shot, developed with Oxford University, was 100% effective against severe or critical forms of the disease. It also said the vaccine showed 85% efficacy in adults 65 years and older.

“A lot of us were waiting for this large, well-constructed and reported Phase III study,” said Paul Griffin, a professor at the University of Queensland.

“This appears to be a very effective vaccine with no safety concerns. Hopefully, this should now give people the confidence that this vaccine is the right one to continue to use moving forward,” he said, adding that he and his parents have taken the vaccine.

The updated 76% efficacy rate compares with rates of about 95% for vaccines from Pfizer/BioNTech and Moderna.The AstraZeneca vaccine is, however, seen as crucial in tackling the spread of COVID-19 across the globe, not just due to limited vaccine supply but also because it is easier and cheaper to transport than rival shots. It has been granted conditional marketing or emergency use authorisation in more than 70 countries.

The highly unusual rebuke from U.S. health authorities had marked a fresh setback for the vaccine that was once hailed as a milestone in the fight against the COVID-19 pandemic, but has been dogged by questions over its effectiveness and possible side-effects.

The shot has faced questions since late last year when the drugmaker and Oxford University published data from an earlier trial with two different efficacy readings as a result of a dosing error.

Then this month, more than a dozen countries temporarily suspended giving out the vaccine after reports linked it to a rare blood clotting disorder in a very small number of people.

The European Union’s drug regulator said last week the vaccine was clearly safe, but Europeans remain sceptical about its safety.

https://www.reuters.com/article/us-health-coronavirus-astrazeneca-usa/astrazeneca-covid-19-vaccine-76-effective-in-updated-u-s-trial-results-idUSKBN2BH03H

Early or Late Lockdowns and Spread of COVID-19 in US Counties

 Xiaolin Huang,  

View ORCID ProfileXiaojian Shao,  View ORCID ProfileLi Xing, Yushan Hu, Don D. Sin,  View ORCID ProfileXuekui Zhang

doi: https://doi.org/10.1101/2021.03.19.21253997

This article is a preprint and has not been certified by peer review [what does this mean?]. It reports new medical research that has yet to be evaluated and so should not be used to guide clinical practice.

PDF: https://www.medrxiv.org/content/10.1101/2021.03.19.21253997v1.full.pdf

 ABSTRACT

Background COVID-19 is a highly transmissible infectious disease that has infected over 122 million individuals worldwide. To combat this pandemic, governments around the world have imposed lockdowns. However, the impact of these lockdowns on the rates of COVID-19 transmission in communities is not well known. Here, we used COVID-19 case counts from 3,000+ counties in the United States (US) to determine the relationship between lockdown as well as other county factors and the rate of COVID-19 spread in these communities.

Methods We merged county-specific COVID-19 case counts with US census data and the date of lockdown for each of the counties. We then applied a Functional Principal Component (FPC) analysis on this dataset to generate scores that described the trajectory of COVID-19 spread across the counties. We used machine learning methods to identify important factors in the county including the date of lockdown that significantly influenced the FPC scores.

Findings We found that the first FPC score accounted for up to 92.81% of the variations in the absolute rates of COVID-19 as well as the topology of COVID-19 spread over time at a county level. The relation between incidence of COVID-19 and time at a county level demonstrated a hockey-stick appearance with an inflection point approximately 7 days prior to the county reporting at least 5 new cases of COVID-19; beyond this inflection point, there was an exponential increase in incidence. Among the risk factors, lockdown and total population were the two most significant features of the county that influenced the rate of COVID-19 infection, while the median family income, median age and within-county move also substantially affect COVID spread.

Interpretation Lockdowns are an effective way of controlling the COVID-19 spread in communities. However, significant delays in lockdown cause a dramatic increase in the case counts. Thus, the timing of the lockdown relative to the case count is an important consideration in controlling the pandemic in communities.

Evidence before this study We searched PubMed using the term “coronavirus”, OR “COVID-19”, OR “COVID-19 infection”, OR “SARS-CoV-2” combined with “Lockdown” or “sociodemographic factor” or “Vulnerability” for original articles published before March 18, 2021. Similar searches were done in medRxiv, Google Scholar, and Web of Science. Only papers published in English were reviewed. The most similar relevant works to our study were Acharya et al.1 and Karmakar et al.2, which investigated the associations between population-level social factors and COVID-19 incidence and mortality. Unlike our current study, which employed a longitudinal design, both of studies were cross-sectional in nature and thus fixed on a single time point. In addition, neither of these studies investigated the impact of lockdown measures on COVID-19 infection patterns. Another relevant study is Alfano et al.’s work3, which focused on the efficacy of lockdown on COVID-19 case rates. However, this study did not evaluate the timing of lockdown on this endpoint.

Added value of this study To our knowledge, this is the first study to use functional principal component analysis (FPCA) to investigate COVID-19 infection trajectories (in a longitudinal manner) and their relationships with different sociodemographic factors and lockdown policy at a county level. The FPCA transformed a longitudinal vector with high-dimensions into a “single” surrogate variable, which retained 93% of the information. We used an advanced statistical model (segmented regression) to investigate the effects of lockdown on incidence of COVID-19 across the US. We found that the relationship had a “hockey stick” appearance with an inflection point at ∼7 days prior to a county reporting at least 5 cases of COVID-19. We also applied a machine learning model (i.e., elastic net) to explore joint effects of lockdown and other sociodemographic factors on COVID-19 infection patterns, which estimated the impact of each of factors, adjusted for each other.

Implications of all the available evidence Our study suggests that lockdown is an effective policy to reduce case counts of COVID-19 in communities; however, significant delays in its implementation result in exponential growth of COVID-19. The inflection point is approximately 7 days prior to a county reporting at least 5 cases of COVID-19. These data will help policy-makers to determine the optimal timing of lockdowns for their communities.

Competing Interest Statement

Don Sin: Professor Sin reports grants from Merck, personal fees from Sanofi-Aventis, personal fees from Regeneron, grants and personal fees from Boehringer Ingelheim, grants and personal fees from AstraZeneca, personal fees from Novartis, outside the submitted work.

Funding Statement

Dr. Xuekui Zhang is funded by Canada Research Chairs. Grant Number: 950‐231363 and Natural Sciences and Engineering Research Council of Canada. Grant Number: RGPIN‐2017‐04722. This research was enabled in part by support provided by WestGrid (www.westgrid.ca) and Compute Canada (www.computecanada.ca). The computing resource is provided by Compute Canada Resource Allocation Competitions #3495 (PI: Xuekui Zhang) and #1551 (PI: Li Xing). Dr. Don Sin is a Tier 1 Canada Research Chair in COPD and holds the de Lazzari Family Chair at the Heart Lung Innovation, Vancouver, Canada.

https://www.medrxiv.org/content/10.1101/2021.03.19.21253997v1

Neutralization of European, S. African, and U.S. SARS-CoV-2 mutants by human antibody and antibody domains

  

View ORCID ProfileZehua Sun, Andrew Kim, Michele D Sobolewski, Nathan Enick, Chuan Chen, Cynthia Adams, Jana L Jacobs, Kevin D McCormick, John W. Mellors, Dimiter S Dimitrov, Wei Li

doi: https://doi.org/10.1101/2021.03.22.436481

This article is a preprint and has not been certified by peer review [what does this mean?].

PDF: https://www.biorxiv.org/content/10.1101/2021.03.22.436481v1.full.pdf

Abstract

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) transmission with several emerging variants remain uncontrolled in many countries, indicating the pandemic remains severe. Recent studies showed reduction of neutralization against these emerging SARS-CoV-2 variants by vaccine-elicited antibodies. Among those emerging SARS-CoV-2 variants, a panel of amino acid mutations was characterized including those in the receptor-binding domain (RBD) of the SARS-CoV-2 spike (S) glycoprotein. In the present study, we evaluated our previously identified antibody and antibody domains for binding to these RBD variants with the emerging mutations, and neutralization of pseudo typed viruses carrying spike proteins with such mutations. Our results showed that one previously identified antibody domain, ab6, can bind 32 out of 35 RBD mutants tested in an ELISA assay. All three antibodies and antibody domains can neutralize pseudo typed B.1.1.7 (UK variant), but only the antibody domain ab6 can neutralize the pseudo typed virus with the triple mutation (K417N, E484K, N501Y). This domain and its improvements have potential for therapy of infections caused by SARS-CoV-2 mutants.

Competing Interest Statement

Z.S., C.C., J.W.M., D.S.D., and W.L. are co-inventors of a patent, US Patent 10,822,379, filed by the University of Pittsburgh on March 12, 2020, related to antibodies described in this paper. J.W.M. and D.S.D. are employed by Abound Bio, a company which is developing some of the antibodies for human use.

https://www.biorxiv.org/content/10.1101/2021.03.22.436481v1

Factors Associated with Emerging and Re-emerging of SARS-CoV-2 Variants

 Austin N Spratt, Saathvik K Kannan,  

View ORCID ProfileLucas T Woods,  View ORCID ProfileGary A Weisman, Thomas D Quinn,  View ORCID ProfileChristian L Lorson,  View ORCID ProfileAnders Sonnerborg, Siddappa N Byrareddy,  View ORCID ProfileKamal Singh

doi: https://doi.org/10.1101/2021.03.24.436850

This article is a preprint and has not been certified by peer review [what does this mean?].

PDF: https://www.biorxiv.org/content/10.1101/2021.03.24.436850v1.full.pdf

Abstract

Global spread of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) has triggered unprecedented scientific efforts, as well as containment and treatment measures. Despite these efforts, SARS-CoV-2 infections remain unmanageable in some parts of the world. Due to inherent mutability of RNA viruses, it is not surprising that the SARS-CoV-2 genome has been continuously evolving since its emergence. Recently, four functionally distinct variants, B.1.1.7, B.1.351, P.1 and CAL.20C, have been identified, and they appear to more infectious and transmissible than the original (Wuhan-Hu-1) virus. Here we provide evidence based upon a combination of bioinformatics and structural approaches that can explain the higher infectivity of the new variants. Our results show that the greater infectivity of SARS-CoV-2 than SARS-CoV can be attributed to a combination of several factors, including alternate receptors. Additionally, we show that new SARS-CoV-2 variants emerged in the background of D614G in Spike protein and P323L in RNA polymerase. The correlation analyses showed that all mutations in specific variants did not evolve simultaneously. Instead, some mutations evolved most likely to compensate for the viral fitness.

Competing Interest Statement

The authors have declared no competing interest.

https://www.biorxiv.org/content/10.1101/2021.03.24.436850v1

Why Did BofA Downgrade Bausch Health?

 There are challenges to value creation in the proposed separation of Bausch Health Companies Inc’s 

BHC 2.97% Bausch and Lomb (B&L) unit and RemainCo, which will be pharma-focused, according to BofA Securities.

The Bausch Health Analyst: Jason Gerberry downgraded the rating for Bausch Health from Neutral to Underperform, while reducing the price target from $33 to $27.

The Bausch Health Thesis: The remaining company, after spinning off the B&L unit, will face “risk of multiple compression” as it is highly levered to Xifaxan, Gerberry said in the downgrade note.

While Xifaxan “has not shown signs of C19 recovery (1Q21: -5% Y/Y),” the recent Medicaid cap removal could limit the drug’s future pricing power, he added. The analyst further noted that the company’s pharma pipeline “has failed to diversify.”

“BHC is already pricing in favorable outcomes in a multi-step separation including favorable divestiture valuations, C19 portfolio recovery, negligible impact to Xifaxan from Medicaid rebate changes and a very sizeable B&L spin at premium multiple," Gerberry wrote, "and recent CFO succession comes at an odd time.”

CFO Paul S. Herendeen was appointed to a newly created role of advisor to the chairman and CEO of Bausch Health, effective June 1, 2021. He is succeeded by Sam Eldessouky, currently senior vice president, controller and chief accounting officer of Bausch Health.

Latest Ratings for BHC

Date	Firm	Action	From	To
Mar 2021	B of A Securities	Downgrades	Neutral	Underperform
Mar 2021	HC Wainwright & Co.	Maintains		Buy
Feb 2021	Morgan Stanley	Maintains		Equal-Weight https://www.benzinga.com/analyst-ratings/analyst-color/21/03/20320376/why-did-bofa-downgrade-bausch-health