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1: Uncanny similarity of unique inserts in the 2019-nCoV spike protein to HIV-1 gp120 and Gag
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Posted 31 Jan 2020

Uncanny similarity of unique inserts in the 2019-nCoV spike protein to HIV-1 gp120 and Gag
1,656,167 downloads bioRxiv evolutionary biology

Prashant Pradhan, Ashutosh Kumar Pandey, Akhilesh Mishra, Parul Gupta, Praveen Kumar Tripathi, Manoj Balakrishnan Menon, James Gomes, Perumal Vivekanandan, Bishwajit Kundu

This paper has been withdrawn by its authors. They intend to revise it in response to comments received from the research community on their technical approach and their interpretation of the results. If you have any questions, please contact the corresponding author.

2: Comparing SARS-CoV-2 natural immunity to vaccine-induced immunity: reinfections versus breakthrough infections
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Posted 25 Aug 2021

Comparing SARS-CoV-2 natural immunity to vaccine-induced immunity: reinfections versus breakthrough infections
992,858 downloads medRxiv infectious diseases

Sivan Gazit, Roei Shlezinger, Galit Perez, Roni Lotan, Asaf Peretz, Amir Ben-Tov, Dani Cohen, Khitam Muhsen, Gabriel Chodick, Tal Patalon

Background: Reports of waning vaccine-induced immunity against COVID-19 have begun to surface. With that, the comparable long-term protection conferred by previous infection with SARS-CoV-2 remains unclear. Methods: We conducted a retrospective observational study comparing three groups: (1)SARS-CoV-2-naive individuals who received a two-dose regimen of the BioNTech/Pfizer mRNA BNT162b2 vaccine, (2)previously infected individuals who have not been vaccinated, and (3)previously infected and single dose vaccinated individuals. Three multivariate logistic regression models were applied. In all models we evaluated four outcomes: SARS-CoV-2 infection, symptomatic disease, COVID-19-related hospitalization and death. The follow-up period of June 1 to August 14, 2021, when the Delta variant was dominant in Israel. Results: SARS-CoV-2-naive vaccinees had a 13.06-fold (95% CI, 8.08 to 21.11) increased risk for breakthrough infection with the Delta variant compared to those previously infected, when the first event (infection or vaccination) occurred during January and February of 2021. The increased risk was significant (P<0.001) for symptomatic disease as well. When allowing the infection to occur at any time before vaccination (from March 2020 to February 2021), evidence of waning natural immunity was demonstrated, though SARS-CoV-2 naive vaccinees had a 5.96-fold (95% CI, 4.85 to 7.33) increased risk for breakthrough infection and a 7.13-fold (95% CI, 5.51 to 9.21) increased risk for symptomatic disease. SARS-CoV-2-naive vaccinees were also at a greater risk for COVID-19-related-hospitalizations compared to those that were previously infected. Conclusions: This study demonstrated that natural immunity confers longer lasting and stronger protection against infection, symptomatic disease and hospitalization caused by the Delta variant of SARS-CoV-2, compared to the BNT162b2 two-dose vaccine-induced immunity. Individuals who were both previously infected with SARS-CoV-2 and given a single dose of the vaccine gained additional protection against the Delta variant.

3: Aerosol and surface stability of HCoV-19 (SARS-CoV-2) compared to SARS-CoV-1
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Posted 10 Mar 2020

Aerosol and surface stability of HCoV-19 (SARS-CoV-2) compared to SARS-CoV-1
942,526 downloads medRxiv infectious diseases

Neeltje A van Doremalen, Trenton Bushmaker, Dylan H. Morris, Myndi G Holbrook, Amandine Gamble, Brandi N. Williamson, Azaibi Tamin, Jennifer L. Harcourt, Natalie J. Thornburg, Susan I. Gerber, James O Lloyd-Smith, Emmie de Wit, Vincent Munster

To the EditorA novel human coronavirus, now named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, referred to as HCoV-19 here) that emerged in Wuhan, China in late 2019 is now causing a pandemic1. Here, we analyze the aerosol and surface stability of HCoV-19 and compare it with SARS-CoV-1, the most closely related human coronavirus.2 We evaluated the stability of HCoV-19 and SARS-CoV-1 in aerosols and on different surfaces and estimated their decay rates using a Bayesian regression model (see Supplementary Appendix). All experimental measurements are reported as mean across 3 replicates.

4: Estimating the effective reproduction number of the 2019-nCoV in China
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Posted 29 Jan 2020

Estimating the effective reproduction number of the 2019-nCoV in China
545,299 downloads medRxiv infectious diseases

Zhidong Cao, Qingpeng Zhang, Xin Lu, Dirk Pfeiffer, Zhongwei Jia, Hongbing Song, Dajun Zeng

We estimate the effective reproduction number for 2019-nCoV based on the daily reported cases from China CDC. The results indicate that 2019-nCoV has a higher effective reproduction number than SARS with a comparable fatality rate. Article Summary LineThis modeling study indicates that 2019-nCoV has a higher effective reproduction number than SARS with a comparable fatality rate.

5: Outcomes of hydroxychloroquine usage in United States veterans hospitalized with Covid-19
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Posted 21 Apr 2020

Outcomes of hydroxychloroquine usage in United States veterans hospitalized with Covid-19
465,718 downloads medRxiv infectious diseases

Joseph Magagnoli, Siddharth Narendran, Felipe Pereira, Tammy Cummings, James W Hardin, S Scott Sutton, Jayakrishna Ambati

BACKGROUND: Despite limited and conflicting data on the use of hydroxychloroquine in patients with Covid-19, the U.S. Food and Drug Administration has authorized the emergency use of this drug when clinical trials are unavailable or infeasible. Hydroxychloroquine, alone or in combination with azithromycin, is being widely used in Covid-19 therapy based on anecdotal and limited observational evidence. METHODS: We performed a retrospective analysis of data from patients hospitalized with confirmed SARS-CoV-2 infection in all United States Veterans Health Administration medical centers until April 11, 2020. Patients were categorized based on their exposure to hydroxychloroquine alone (HC) or with azithromycin (HC+AZ) as treatments in addition to standard supportive management for Covid-19. The two primary outcomes were death and the need for mechanical ventilation. We determined the association between treatment and the primary outcomes using competing risk hazard regression adjusting for clinical characteristics via propensity scores. Discharge and death were taken into account as competing risks and subdistribution hazard ratios are presented. RESULTS: A total of 368 patients were evaluated (HC, n=97; HC+AZ, n=113; no HC, n=158). Rates of death in the HC, HC+AZ, and no HC groups were 27.8%, 22.1%, 11.4%, respectively. Rates of ventilation in the HC, HC+AZ, and no HC groups were 13.3%, 6.9%, 14.1%, respectively. Compared to the no HC group, the risk of death from any cause was higher in the HC group (adjusted hazard ratio, 2.61; 95% CI, 1.10 to 6.17; P=0.03) but not in the HC+AZ group (adjusted hazard ratio, 1.14; 95% CI, 0.56 to 2.32; P=0.72). The risk of ventilation was similar in the HC group (adjusted hazard ratio, 1.43; 95% CI, 0.53 to 3.79; P=0.48) and in the HC+AZ group (adjusted hazard ratio, 0.43; 95% CI, 0.16 to 1.12; P=0.09), compared to the no HC group. CONCLUSIONS: In this study, we found no evidence that use of hydroxychloroquine, either with or without azithromycin, reduced the risk of mechanical ventilation in patients hospitalized with Covid-19. An association of increased overall mortality was identified in patients treated with hydroxychloroquine alone. These findings highlight the importance of awaiting the results of ongoing prospective, randomized, controlled studies before widespread adoption of these drugs.

6: Novel coronavirus 2019-nCoV: early estimation of epidemiological parameters and epidemic predictions
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Posted 24 Jan 2020

Novel coronavirus 2019-nCoV: early estimation of epidemiological parameters and epidemic predictions
394,013 downloads medRxiv infectious diseases

Jonathan M Read, Jessica Bridgen, Derek Cummings, Antonia Ho, Chris Jewell

Since first identified, the epidemic scale of the recently emerged novel coronavirus (2019-nCoV) in Wuhan, China, has increased rapidly, with cases arising across China and other countries and regions. using a transmission model, we estimate a basic reproductive number of 3.11 (95%CI, 2.39-4.13); 58-76% of transmissions must be prevented to stop increasing; Wuhan case ascertainment of 5.0% (3.6-7.4); 21022 (11090-33490) total infections in Wuhan 1 to 22 January. Changes to previous versionO_LIcase data updated to include 22 Jan 2020; we did not use cases reported after this period as cases were reported at the province level hereafter, and large-scale control interventions were initiated on 23 Jan 2020; C_LIO_LIimproved likelihood function, better accounting for first 41 confirmed cases, and now using all infections (rather than just cases detected) in Wuhan for prediction of infection in international travellers; C_LIO_LIimproved characterization of uncertainty in parameters, and calculation of epidemic trajectory confidence intervals using a more statistically rigorous method; C_LIO_LIextended range of latent period in sensitivity analysis to reflect reports of up to 6 day incubation period in household clusters; C_LIO_LIremoved travel restriction analysis, as different modelling approaches (e.g. stochastic transmission, rather than deterministic transmission) are more appropriate to such analyses. C_LI

7: Correlation between universal BCG vaccination policy and reduced morbidity and mortality for COVID-19: an epidemiological study
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Posted 28 Mar 2020

Correlation between universal BCG vaccination policy and reduced morbidity and mortality for COVID-19: an epidemiological study
360,617 downloads medRxiv epidemiology

Aaron Miller, Mac Josh Reandelar, Kimberly Fasciglione, Violeta Roumenova, Yan Li, Gonzalo H Otazu

COVID-19 has spread to most countries in the world. Puzzlingly, the impact of the disease is different in different countries. These differences are attributed to differences in cultural norms, mitigation efforts, and health infrastructure. Here we propose that national differences in COVID- 19 impact could be partially explained by the different national policies respect to Bacillus Calmette-Guerin (BCG) childhood vaccination. BCG vaccination has been reported to offer broad protection to respiratory infections. We compared large number of countries BCG vaccination policies with the morbidity and mortality for COVID-19. We found that countries without universal policies of BCG vaccination (Italy, Nederland, USA) have been more severely affected compared to countries with universal and long-standing BCG policies. Countries that have a late start of universal BCG policy (Iran, 1984) had high mortality, consistent with the idea that BCG protects the vaccinated elderly population. We also found that BCG vaccination also reduced the number of reported COVID-19 cases in a country. The combination of reduced morbidity and mortality makes BCG vaccination a potential new tool in the fight against COVID-19.

8: Heterologous SARS-CoV-2 Booster Vaccinations: Preliminary Report
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Posted 13 Oct 2021

Heterologous SARS-CoV-2 Booster Vaccinations: Preliminary Report
302,497 downloads medRxiv infectious diseases

Robert L. Atmar, Kirsten E. Lyke, Meagan E Deming, Lisa A. Jackson, Angela R. Branche, Hana M. El Sahly, Christina A. Rostad, Judith M Martin, Christine Johnston, Richard E Rupp, Mark J Mulligan, Rebecca C Brady, Robert W Frenck, Martin Backer, Angelica C Kottkamp, Tara M Babu, Kumaravel Rajakumar, Srilatha Edupuganti, David Dobryzynski, Christine M. Posavad, Janet I Archer, Sonja Crandon, Seema U Nayak, Daniel Szydlo, Jillian Zemanek, Clara P Dominguez Islas, Elizabeth R. Brown, Mehul S Suthar, M. Juliana McElrath, Adrian B. McDermott, Sarah E O'Connell, David C. Montefiori, Amanda Eaton, Kathleen M. Neuzil, David S Stephens, Paul C. Roberts, John Beigel

Background: 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: In this phase 1/2 open-label clinical trial conducted at ten U.S. sites, adults who received one of three EUA Covid-19 vaccines at least 12 weeks prior to enrollment and had no reported history of SARS-CoV-2 infection received a booster injection with one of three vaccines (Moderna mRNA-1273 100-mcg, Janssen Ad26.COV2.S 5x1010 virus particles, or Pfizer-BioNTech BNT162b2 30-mcg; nine combinations). The primary outcomes were safety, reactogenicity, and humoral immunogenicity on study days 15 and 29. Results: 458 individuals were enrolled: 154 received mRNA-1273, 150 received Ad26.CoV2.S, and 154 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: 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.

9: Discovery of a novel coronavirus associated with the recent pneumonia outbreak in humans and its potential bat origin
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Posted 23 Jan 2020

Discovery of a novel coronavirus associated with the recent pneumonia outbreak in humans and its potential bat origin
300,190 downloads bioRxiv microbiology

Peng Zhou, Xing-Lou Yang, Xian-Guang Wang, Ben Hu, Lei Zhang, Wei Zhang, Hao-Rui Si, Yan Zhu, Bei Li, Chao-Lin Huang, Hui-Dong Chen, Jing Chen, Yun Luo, Hua Guo, Ren-Di Jiang, Mei-Qin Liu, Ying Chen, Xu-Rui Shen, Xi Wang, Xiao-Shuang Zheng, Kai Zhao, Quan-Jiao Chen, Fei Deng, Lin-Lin Liu, Bing Yan, Fa-Xian Zhan, Yan-Yi Wang, Gengfu Xiao, Zheng-Li Shi

Since the SARS outbreak 18 years ago, a large number of severe acute respiratory syndrome related coronaviruses (SARSr-CoV) have been discovered in their natural reservoir host, bats. Previous studies indicated that some of those bat SARSr-CoVs have the potential to infect humans. Here we report the identification and characterization of a novel coronavirus (nCoV-2019) which caused an epidemic of acute respiratory syndrome in humans, in Wuhan, China. The epidemic, started from December 12th, 2019, has caused 198 laboratory confirmed infections with three fatal cases by January 20th, 2020. Full-length genome sequences were obtained from five patients at the early stage of the outbreak. They are almost identical to each other and share 79.5% sequence identify to SARS-CoV. Furthermore, it was found that nCoV-2019 is 96% identical at the whole genome level to a bat coronavirus. The pairwise protein sequence analysis of seven conserved non-structural proteins show that this virus belongs to the species of SARSr-CoV. The nCoV-2019 virus was then isolated from the bronchoalveolar lavage fluid of a critically ill patient, which can be neutralized by sera from several patients. Importantly, we have confirmed that this novel CoV uses the same cell entry receptor, ACE2, as SARS-CoV.

10: Report of Partial findings from the National Toxicology Program Carcinogenesis Studies of Cell Phone Radiofrequency Radiation in Hsd: Sprague Dawley® SD rats (Whole Body Exposure)
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Posted 26 May 2016

Report of Partial findings from the National Toxicology Program Carcinogenesis Studies of Cell Phone Radiofrequency Radiation in Hsd: Sprague Dawley® SD rats (Whole Body Exposure)
294,978 downloads bioRxiv cancer biology

Michael Wyde, Mark Cesta, Chad Blystone, Susan Elmore, Paul Foster, Michelle Hooth, Grace Kissling, David Malarkey, Robert Sills, Matthew Stout, Nigel Walker, Kristine Witt, Mary Wolfe, John Bucher

The U.S. National Toxicology Program (NTP) has carried out extensive rodent toxicology and carcinogenesis studies of radiofrequency radiation (RFR) at frequencies and modulations used in the U.S. telecommunications industry. This report presents partial findings from these studies. The occurrences of two tumor types in male Harlan Sprague Dawley rats exposed to RFR, malignant gliomas in the brain and schwannomas of the heart, were considered of particular interest and are the subject of this report. The findings in this report were reviewed by expert peer reviewers selected by the NTP and National Institutes of Health (NIH). These reviews and responses to comments are included as appendices to this report, and revisions to the current document have incorporated and addressed these comments. When the studies are completed, they will undergo additional peer review before publication in full as part of the NTP's Toxicology and Carcinogenesis Technical Reports Series. No portion of this work has been submitted for publication in a scientific journal. Supplemental information in the form of four additional manuscripts has or will soon be submitted for publication. These manuscripts describe in detail the designs and performance of the RFR exposure system, the dosimetry of RFR exposures in rats and mice, the results to a series of pilot studies establishing the ability of the animals to thermoregulate during RFR exposures, and studies of DNA damage. (1) Capstick M, Kuster N, Kuhn S, Berdinas-Torres V, Wilson P, Ladbury J, Koepke G, McCormick D, Gauger J, and Melnick R. A radio frequency radiation reverberation chamber exposure system for rodents; (2) Yijian G, Capstick M, McCormick D, Gauger J, Horn T, Wilson P, Melnick RL, and Kuster N. Life time dosimetric assessment for mice and rats exposed to cell phone radiation; (3) Wyde ME, Horn TL, Capstick M, Ladbury J, Koepke G, Wilson P, Stout MD, Kuster N, Melnick R, Bucher JR, and McCormick D. Pilot studies of the National Toxicology Program's cell phone radiofrequency radiation reverberation chamber exposure system; (4) Smith-Roe SL, Wyde ME, Stout MD, Winters J, Hobbs CA, Shepard KG, Green A, Kissling GE, Tice RR, Bucher JR, and Witt KL. Evaluation of the genotoxicity of cell phone radiofrequency radiation in male and female rats and mice following subchronic exposure.

11: Vaccine effectiveness against SARS-CoV-2 infection with the Omicron or Delta variants following a two-dose or booster BNT162b2 or mRNA-1273 vaccination series: A Danish cohort study
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Posted 21 Dec 2021

Vaccine effectiveness against SARS-CoV-2 infection with the Omicron or Delta variants following a two-dose or booster BNT162b2 or mRNA-1273 vaccination series: A Danish cohort study
292,034 downloads medRxiv infectious diseases

Christian Holm Hansen, Astrid Blicher Schelde, Ida Rask Moustsen-Helms, Hanne-Dorthe Emborg, Tyra Grove Krause, Kåre Mølbak, Palle Valentiner-Branth, The Infectious Disease Preparedness Group at Statens Serum Institut

In this brief communication we are showing original research results with early estimates from Danish nationwide databases of vaccine effectiveness (VE) against the novel SARS-CoV-2 Omicron variant (B.1.1.529) up to five months after a primary vaccination series with the BNT162b2 or mRNA-1273 vaccines. Our study provides evidence of protection against infection with the Omicron variant after completion of a primary vaccination series with the BNT162b2 or mRNA-1273 vaccines; in particular, we found a VE against the Omicron variant of 55.2% (95% confidence interval (CI): 23.5 to 73.7%) and 36.7% (95% CI: -69.9 to 76.4%) for the BNT162b2 and mRNA-1273 vaccines, respectively, in the first month after primary vaccination. However, the VE is significantly lower than that against Delta infection and declines rapidly over just a few months. The VE is re-established upon revaccination with the BNT162b2 vaccine (54.6%, 95% CI: 30.4 to 70.4%).

12: COVID-19 Antibody Seroprevalence in Santa Clara County, California
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Posted 17 Apr 2020

COVID-19 Antibody Seroprevalence in Santa Clara County, California
291,750 downloads medRxiv epidemiology

Eran Bendavid, Bianca Mulaney, Neeraj Sood, Soleil Shah, Emilia Ling, Rebecca Bromley-Dulfano, Cara Lai, Zoe Weissberg, Rodrigo Saavedra-Walker, James Tedrow, Dona Tversky, Andrew Bogan, Thomas Kupiec, Daniel Eichner, Ribhav Gupta, John Ioannidis, Jay Bhattacharya

Background Addressing COVID-19 is a pressing health and social concern. To date, many epidemic projections and policies addressing COVID-19 have been designed without seroprevalence data to inform epidemic parameters. We measured the seroprevalence of antibodies to SARS-CoV-2 in a community sample drawn from Santa Clara County. Methods On April 3-4, 2020, we tested county residents for antibodies to SARS-CoV-2 using a lateral flow immunoassay. Participants were recruited using Facebook ads targeting a sample of individuals living within the county by demographic and geographic characteristics. We estimate weights to adjust our sample to match the zip code, sex, and race/ethnicity distribution within the county. We report both the weighted and unweighted prevalence of antibodies to SARS-CoV-2. We also adjust for test performance characteristics by combining data from 16 independent samples obtained from manufacturer's data, regulatory submissions, and independent evaluations: 13 samples for specificity (3,324 specimens) and 3 samples for sensitivity (157 specimens). Results The raw prevalence of antibodies to SARS-CoV-2 in our sample was 1.5% (exact binomial 95CI 1.1-2.0%). Test performance specificity in our data was 99.5% (95CI 99.2-99.7%) and sensitivity was 82.8% (95CI 76.0-88.4%). The unweighted prevalence adjusted for test performance characteristics was 1.2% (95CI 0.7-1.8%). After weighting for population demographics of Santa Clara County, the prevalence was 2.8% (95CI 1.3-4.7%), using bootstrap to estimate confidence bounds. These prevalence point estimates imply that 54,000 (95CI 25,000 to 91,000 using weighted prevalence; 23,000 with 95CI 14,000-35,000 using unweighted prevalence) people were infected in Santa Clara County by early April, many more than the approximately 1,000 confirmed cases at the time of the survey. Conclusions The estimated population prevalence of SARS-CoV-2 antibodies in Santa Clara County implies that the infection may be much more widespread than indicated by the number of confirmed cases. More studies are needed to improve precision of prevalence estimates. Locally-derived population prevalence estimates should be used to calibrate epidemic and mortality projections.

13: Risk of myocarditis following sequential COVID-19 vaccinations by age and sex
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Posted 25 Dec 2021

Risk of myocarditis following sequential COVID-19 vaccinations by age and sex
287,128 downloads medRxiv epidemiology

Martina Patone, Winnie Xue Mei, Lahiru Handunnetthi, Sharon Dixon, Francesco Zaccardi, Manu Shankar-Hari, Peter J Watkinson, Kamlesh Khunti, Anthony Harnden, Carol AC Coupland, Keith M Channon, Nicholas L Mills, Aziz Sheikh, Julia Hippisley-Cox

In an updated self-controlled case series analysis of 42,200,614 people aged 13 years or more, we evaluate the association between COVID-19 vaccination and myocarditis, stratified by age and sex, including 10,978,507 people receiving a third vaccine dose. Myocarditis risk was increased during 1-28 days following a third dose of BNT162b2 (IRR 2.02, 95%CI 1.40, 2.91). Associations were strongest in males younger than 40 years for all vaccine types with an additional 3 (95%CI 1, 5) and 12 (95% CI 1,17) events per million estimated in the 1-28 days following a first dose of BNT162b2 and mRNA-1273, respectively; 14 (95%CI 8, 17), 12 (95%CI 1, 7) and 101 (95%CI 95, 104) additional events following a second dose of ChAdOx1, BNT162b2 and mRNA-1273, respectively; and 13 (95%CI 7, 15) additional events following a third dose of BNT162b2, compared with 7 (95%CI 2, 11) additional events following COVID-19 infection. An association between COVID-19 infection and myocarditis was observed in all ages for both sexes but was substantially higher in those older than 40 years. These findings have important implications for public health and vaccination policy.

14: The SARS-CoV-2 Delta variant is poised to acquire complete resistance to wild-type spike vaccines
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Posted 23 Aug 2021

The SARS-CoV-2 Delta variant is poised to acquire complete resistance to wild-type spike vaccines
276,584 downloads bioRxiv microbiology

Yafei Liu, Noriko Arase, Jun-ishi Kishikawa, Mika Hirose, Songling Li, Asa Tada, Sumiko Matsuoka, Akemi Arakawa, Kanako Akamatsu, Chikako Ono, Hui Jin, Kazuki Kishida, Wataru Nakai, Masako Kohyama, Atsushi Nakagawa, Yoshiaki Yamagishi, Hironori Nakagami, Atsushi Kumanogoh, Yoshiharu Matsuura, Daron M Standley, Takayuki Kato, Masato Okada, Manabu Fujimoto, Hisashi Arase

mRNA-based vaccines provide effective protection against most common SARS-CoV-2 variants. However, identifying likely breakthrough variants is critical for future vaccine development. Here, we found that the Delta variant completely escaped from anti-N-terminal domain (NTD) neutralizing antibodies, while increasing responsiveness to anti-NTD infectivity-enhancing antibodies. Although Pfizer-BioNTech BNT162b2-immune sera neutralized the Delta variant, when four common mutations were introduced into the receptor binding domain (RBD) of the Delta variant (Delta 4+), some BNT162b2-immune sera lost neutralizing activity and enhanced the infectivity. Unique mutations in the Delta NTD were involved in the enhanced infectivity by the BNT162b2-immune sera. Sera of mice immunized by Delta spike, but not wild-type spike, consistently neutralized the Delta 4+ variant without enhancing infectivity. Given the fact that a Delta variant with three similar RBD mutations has already emerged according to the GISAID database, it is necessary to develop vaccines that protect against such complete breakthrough variants.

15: Comparison of two highly-effective mRNA vaccines for COVID-19 during periods of Alpha and Delta variant prevalence
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Posted 08 Aug 2021

Comparison of two highly-effective mRNA vaccines for COVID-19 during periods of Alpha and Delta variant prevalence
270,834 downloads medRxiv public and global health

Arjun Puranik, Patrick J Lenehan, Eli Silvert, Michiel JM Niesen, Juan Corchado-Garcia, John C O'Horo, Abinash Virk, Melanie D Swift, John Halamka, Andrew D Badley, AJ Venkatakrishnan, Venky Soundararajan

Although clinical trials and real-world studies have affirmed the effectiveness and safety of the FDA-authorized COVID-19 vaccines, reports of breakthrough infections and persistent emergence of new variants highlight the need to vigilantly monitor the effectiveness of these vaccines. Here we compare the effectiveness of two full-length Spike protein-encoding mRNA vaccines from Moderna (mRNA-1273) and Pfizer/BioNTech (BNT162b2) in the Mayo Clinic Health System over time from January to July 2021, during which either the Alpha or Delta variant was highly prevalent. We defined cohorts of vaccinated and unvaccinated individuals from Minnesota (n = 25,589 each) matched on age, sex, race, history of prior SARS-CoV-2 PCR testing, and date of full vaccination. Both vaccines were highly effective during this study period against SARS-CoV-2 infection (mRNA-1273: 86%, 95%CI: 81-90.6%; BNT162b2: 76%, 95%CI: 69-81%) and COVID-19 associated hospitalization (mRNA-1273: 91.6%, 95% CI: 81-97%; BNT162b2: 85%, 95% CI: 73-93%). However, in July, the effectiveness against infection was considerably lower for mRNA-1273 (76%, 95% CI: 58-87%) with an even more pronounced reduction in effectiveness for BNT162b2 (42%, 95% CI: 13-62%). Notably, the Delta variant prevalence in Minnesota increased from 0.7% in May to over 70% in July whereas the Alpha variant prevalence decreased from 85% to 13% over the same time period. Comparing rates of infection between matched individuals fully vaccinated with mRNA-1273 versus BNT162b2 across Mayo Clinic Health System sites in multiple states (Minnesota, Wisconsin, Arizona, Florida, and Iowa), mRNA-1273 conferred a two-fold risk reduction against breakthrough infection compared to BNT162b2 (IRR = 0.50, 95% CI: 0.39-0.64). In Florida, which is currently experiencing its largest COVID-19 surge to date, the risk of infection in July after full vaccination with mRNA-1273 was about 60% lower than after full vaccination with BNT162b2 (IRR: 0.39, 95% CI: 0.24-0.62). Our observational study highlights that while both mRNA COVID-19 vaccines strongly protect against infection and severe disease, further evaluation of mechanisms underlying differences in their effectiveness such as dosing regimens and vaccine composition are warranted.

16: The infection fatality rate of COVID-19 inferred from seroprevalence data
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Posted 19 May 2020

The infection fatality rate of COVID-19 inferred from seroprevalence data
261,845 downloads medRxiv infectious diseases

John Ioannidis

Objective To estimate the infection fatality rate of coronavirus disease 2019 (COVID-19) from data of seroprevalence studies. Methods Population studies with sample size of at least 500 and published as peer-reviewed papers or preprints as of July 11, 2020 were retrieved from PubMed, preprint servers, and communications with experts. Studies on blood donors were included, but studies on healthcare workers were excluded. The studies were assessed for design features and seroprevalence estimates. Infection fatality rate was estimated from each study dividing the number of COVID-19 deaths at a relevant time point by the number of estimated people infected in each relevant region. Correction was also attempted accounting for the types of antibodies assessed. Secondarily, results from national studies were also examined from preliminary press releases and reports whenever a country had no other data presented in full papers of preprints. Results 36 studies (43 estimates) were identified with usable data to enter into calculations and another 7 preliminary national estimates were also considered for a total of 50 estimates. Seroprevalence estimates ranged from 0.222% to 47%. Infection fatality rates ranged from 0.00% to 1.63% and corrected values ranged from 0.00% to 1.31%. Across 32 different locations, the median infection fatality rate was 0.27% (corrected 0.24%). Most studies were done in pandemic epicenters with high death tolls. Median corrected IFR was 0.10% in locations with COVID-19 population mortality rate less than the global average (<73 deaths per million as of July 12, 2020), 0.27% in locations with 73-500 COVID-19 deaths per million, and 0.90% in locations exceeding 500 COVID-19 deaths per million. Among people <70 years old, infection fatality rates ranged from 0.00% to 0.57% with median of 0.05% across the different locations (corrected median of 0.04%). Conclusions The infection fatality rate of COVID-19 can vary substantially across different locations and this may reflect differences in population age structure and case-mix of infected and deceased patients as well as multiple other factors. Estimates of infection fatality rates inferred from seroprevalence studies tend to be much lower than original speculations made in the early days of the pandemic.

17: Six Month Safety and Efficacy of the BNT162b2 mRNA COVID-19 Vaccine
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Posted 28 Jul 2021

Six Month Safety and Efficacy of the BNT162b2 mRNA COVID-19 Vaccine
259,417 downloads medRxiv infectious diseases

Stephen J. Thomas, Edson D Moreira, Nicholas Kitchin, Judith Absalon, Alejandra Gurtman, Stephen Lockhart, John L Perez, Gonzalo Pérez Marc, Fernando P. Polack, Cristiano Zerbini, Ruth Bailey, Kena A. Swanson, Xia Xu, Satrajit Roychoudhury, Kenneth Koury, Salim Bouguermouh, Warren V. Kalina, David Cooper, Robert W Frenck, Laura L. Hammitt, Özlem Türeci, Haylene Nell, Axel Schaefer, Serhat Ünal, Qi Yang, Paul Liberator, Dina B Tresnan, Susan Mather, Philip R. Dormitzer, Uğur Şahin, William C. Gruber, Kathrin U. Jansen, C4591001 Clinical Trial Group

Background: BNT162b2 is a lipid nanoparticle-formulated, nucleoside-modified RNA vaccine encoding a prefusion-stabilized, membrane-anchored SARS-CoV-2 full-length spike protein. BNT162b2 is highly efficacious against COVID-19 and is currently authorized for emergency use or conditional approval worldwide. At the time of authorization, data beyond 2 months post-vaccination were unavailable. Methods: In an ongoing, placebo-controlled, observer-blinded, multinational, pivotal efficacy study, 44,165 [&ge;]16-year-old participants and 2,264 12-15-year-old participants were randomized to receive 2 doses, 21 days apart, of 30 g BNT162b2 or placebo. Study endpoints reported here are vaccine efficacy (VE) against laboratory-confirmed COVID-19 and safety data, both up to 6 months post-vaccination. Results: BNT162b2 continued to be safe and well tolerated. Few participants had adverse events leading to study withdrawal. VE against COVID-19 was 91% (95% CI 89.0-93.2) through up to 6 months of follow-up, among evaluable participants and irrespective of previous SARS-CoV-2 infection. VE of 86%-100% was seen across countries and in populations with diverse characteristics of age, sex, race/ethnicity, and COVID-19 risk factors in participants without evidence of previous SARS-CoV-2 infection. VE against severe disease was 97% % (95% CI 80.3-99.9). In South Africa, where the SARS-CoV-2 variant of concern, B.1.351 (beta), was predominant, 100% (95% CI 53.5, 100.0) VE was observed. Conclusion: With up to 6 months of follow-up and despite a gradually declining trend in vaccine efficacy, BNT162b2 had a favorable safety profile and was highly efficacious in preventing COVID-19. (ClinicalTrials.gov number, NCT04368728)

18: Spike mutation pipeline reveals the emergence of a more transmissible form of SARS-CoV-2
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Posted 30 Apr 2020

Spike mutation pipeline reveals the emergence of a more transmissible form of SARS-CoV-2
256,886 downloads bioRxiv evolutionary biology

Bette Korber, Will Fischer, S. Gnanakaran, H Yoon, J Theiler, W Abfalterer, Brian T. Foley, EE Giorgi, T Bhattacharya, MD Parker, DG Partridge, CM Evans, TM Freeman, Thushan I de Silva, on behalf of the Sheffield COVID-19 Genomics Group, Celia LaBranche, David C. Montefiori

We have developed an analysis pipeline to facilitate real-time mutation tracking in SARS-CoV-2, focusing initially on the Spike (S) protein because it mediates infection of human cells and is the target of most vaccine strategies and antibody-based therapeutics. To date we have identified fourteen mutations in Spike that are accumulating. Mutations are considered in a broader phylogenetic context, geographically, and over time, to provide an early warning system to reveal mutations that may confer selective advantages in transmission or resistance to interventions. Each one is evaluated for evidence of positive selection, and the implications of the mutation are explored through structural modeling. The mutation Spike D614G is of urgent concern; after beginning to spread in Europe in early February, when introduced to new regions it repeatedly and rapidly becomes the dominant form. Also, we present evidence of recombination between locally circulating strains, indicative of multiple strain infections. These finding have important implications for SARS-CoV-2 transmission, pathogenesis and immune interventions. ### Competing Interest Statement The authors have declared no competing interest.

19: Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial
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Posted 30 Mar 2020

Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial
254,198 downloads medRxiv epidemiology

Zhaowei Chen, Jijia Hu, Zongwei Zhang, Shan Jiang, Shoumeng Han, Dandan Yan, Ruhong Zhuang, Ben Hu, Zhan Zhang

AimsStudies have indicated that chloroquine (CQ) shows antagonism against COVID-19 in vitro. However, evidence regarding its effects in patients is limited. This study aims to evaluate the efficacy of hydroxychloroquine (HCQ) in the treatment of patients with COVID-19. Main methodsFrom February 4 to February 28, 2020, 62 patients suffering from COVID-19 were diagnosed and admitted to Renmin Hospital of Wuhan University. All participants were randomized in a parallel-group trial, 31 patients were assigned to receive an additional 5-day HCQ (400 mg/d) treatment, Time to clinical recovery (TTCR), clinical characteristics, and radiological results were assessed at baseline and 5 days after treatment to evaluate the effect of HCQ. Key findingsFor the 62 COVID-19 patients, 46.8% (29 of 62) were male and 53.2% (33 of 62) were female, the mean age was 44.7 (15.3) years. No difference in the age and sex distribution between the control group and the HCQ group. But for TTCR, the body temperature recovery time and the cough remission time were significantly shortened in the HCQ treatment group. Besides, a larger proportion of patients with improved pneumonia in the HCQ treatment group (80.6%, 25 of 31) compared with the control group (54.8%, 17 of 31). Notably, all 4 patients progressed to severe illness that occurred in the control group. However, there were 2 patients with mild adverse reactions in the HCQ treatment group. Significance: Among patients with COVID-19, the use of HCQ could significantly shorten TTCR and promote the absorption of pneumonia. SignificanceAmong patients with COVID-19, the use of HCQ could significantly shorten TTCR and promote the absorption of pneumonia. Trial registrationURL: https://www.clinicaltrials.gov/. The unique identifier: ChiCTR2000029559.

20: Transmission Potential of SARS-CoV-2 in Viral Shedding Observed at the University of Nebraska Medical Center
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Posted 26 Mar 2020

Transmission Potential of SARS-CoV-2 in Viral Shedding Observed at the University of Nebraska Medical Center
240,851 downloads medRxiv infectious diseases

Joshua L Santarpia, Danielle N Rivera, Vicki Herrera, M. Jane Morwitzer, Hannah Creager, George W. Santarpia, Kevin K Crown, David Brett-Major, Elizabeth Schnaubelt, M. Jana Broadhurst, James V. Lawler, St Patrick Reid, John J. Lowe

Lack of evidence on SARS-CoV-2 transmission dynamics has led to shifting isolation guidelines between airborne and droplet isolation precautions. During the initial isolation of 13 individuals confirmed positive with COVID-19 infection, air and surface samples were collected in eleven isolation rooms to examine viral shedding from isolated individuals. While all individuals were confirmed positive for SARS-CoV-2, symptoms and viral shedding to the environment varied considerably. Many commonly used items, toilet facilities, and air samples had evidence of viral contamination, indicating that SARS-CoV-2 is shed to the environment as expired particles, during toileting, and through contact with fomites. Disease spread through both direct (droplet and person-to-person) as well as indirect contact (contaminated objects and airborne transmission) are indicated, supporting the use of airborne isolation precautions. One Sentence SummarySARS-CoV-2 is shed during respiration, toileting, and fomite contact, indicating that infection may occur in both direct and indirect contact.

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