SARS-CoV-2 Sequence Characteristics of COVID-19 Persistence and Reinfection

  

View ORCID ProfileManish C. Choudhary, Charles R. Crain, Xueting Qiu, William Hanage, Jonathan Z. Li

doi: https://doi.org/10.1101/2021.03.02.21252750

This article is a preprint and has not been peer-reviewed [what does this mean?].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/10.1101/2021.03.02.21252750v2.full.pdf

ABSTRACT

Background Both SARS-CoV-2 reinfection and persistent infection have been reported, but sequence characteristics in these scenarios have not been described. We assessed published cases of SARS-CoV-2 reinfection and persistence, characterizing the hallmarks of reinfecting sequences and the rate of viral evolution in persistent infection.

Methods A systematic review of PubMed was conducted to identify cases of SARS-CoV-2 reinfection and persistence with available sequences. Nucleotide and amino acid changes in the reinfecting sequence were compared to both the initial and contemporaneous community variants. Time-measured phylogenetic reconstruction was performed to compare intra-host viral evolution in persistent SARS-CoV-2 to community-driven evolution.

Results Twenty reinfection and nine persistent infection cases were identified. Reports of reinfection cases spanned a broad distribution of ages, baseline health status, reinfection severity, and occurred as early as 1.5 months or >8 months after the initial infection. The reinfecting viral sequences had a median of 17.5 nucleotide changes with enrichment in the ORF8 and N genes. The number of changes did not differ by the severity of reinfection and reinfecting variants were similar to the contemporaneous sequences circulating in the community. Patients with persistent COVID-19 demonstrated more rapid accumulation of sequence changes than seen with community-driven evolution with continued evolution during convalescent plasma or monoclonal antibody treatment.

Conclusions Reinfecting SARS-CoV-2 viral genomes largely mirror contemporaneous circulating sequences in that geographic region, while persistent COVID-19 has been largely described in immunosuppressed individuals and is associated with accelerated viral evolution.

Summary Reinfecting SARS-CoV-2 viral genomes largely mirror contemporaneous circulating sequences in that geographic region, while persistent COVID-19 has been largely described in immunosuppressed individuals and is associated with accelerated viral evolution.

Funding This study was funded in part by the NIH grant 106701.

Disclosures Dr. Li has consulted for Abbvie.

https://www.medrxiv.org/content/10.1101/2021.03.02.21252750v2.full

A SARS CoV-2 nucleocapsid vaccine protects against distal viral dissemination

 Jacob Class, Tanushree Dangi, Justin M. Richner,  

View ORCID ProfilePablo Penaloza-MacMaster

doi: https://doi.org/10.1101/2021.04.26.440920

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

PDF: https://www.biorxiv.org/content/10.1101/2021.04.26.440920v1.full.pdf

Abstract

The SARS CoV-2 pandemic has killed millions of people. This viral infection can also result in substantial morbidity, including respiratory insufficiency and neurological manifestations, such as loss of smell and psychiatric diseases. Most SARS CoV-2 vaccines are based on the spike antigen, and although they have shown extraordinary efficacy at preventing severe lung disease and death, they do not always confer sterilizing immune protection. We performed studies in K18-hACE2 mice to evaluate whether the efficacy of SARS CoV-2 vaccines could be augmented by incorporating nucleocapsid as a vaccine antigen. We vaccinated mice with adenovirus-based vaccines encoding spike antigen alone, nucleocapsid antigen alone, or combined spike and nucleocapsid antigens. Mice were then challenged intranasally with SARS CoV-2, and acute viral loads were quantified at a proximal site of infection (lung) and a distal site of infection (brain). Interestingly, the spike-based vaccine conferred acute protection in the lung, but not in the brain. The spike-based vaccine conferred acute protection in the brain only if combined with the nucleocapsid-based vaccine. These findings suggest that nucleocapsid-specific immunity is important for the distal control of SARS CoV-2, warranting the inclusion of nucleocapsid in next-generation COVID-19 vaccines.

Competing Interest Statement

Pablo Penaloza-MacMaster reports being Task Force Advisor to the Illinois Department of Public Health (IDPH) on SARS CoV-2 vaccines. Pablo Penaloza-MacMaster is also advisor of the COVID-19 Vaccine Regulatory Science Consortium (CoVAXCEN) at Northwestern University Institute for Global Health

https://www.biorxiv.org/content/10.1101/2021.04.26.440920v1

Efficacy of Ivermectin in the Prophylaxis and Treatment of COVID-19

 Kory, Pierre MD^1,*; Meduri, Gianfranco Umberto MD²; Varon, Joseph MD³; Iglesias, Jose DO⁴; Marik, Paul E. MD

doi: 10.1097/MJT.0000000000001377

Abstract

Background: 

After COVID-19 emerged on U.S shores, providers began reviewing the emerging basic science, translational, and clinical data to identify potentially effective treatment options. In addition, a multitude of both novel and repurposed therapeutic agents were used empirically and studied within clinical trials.

Areas of Uncertainty: 

The majority of trialed agents have failed to provide reproducible, definitive proof of efficacy in reducing the mortality of COVID-19 with the exception of corticosteroids in moderate to severe disease. Recently, evidence has emerged that the oral antiparasitic agent ivermectin exhibits numerous antiviral and anti-inflammatory mechanisms with trial results reporting significant outcome benefits. Given some have not passed peer review, several expert groups including Unitaid/World Health Organization have undertaken a systematic global effort to contact all active trial investigators to rapidly gather the data needed to grade and perform meta-analyses.

Data Sources: 

Data were sourced from published peer-reviewed studies, manuscripts posted to preprint servers, expert meta-analyses, and numerous epidemiological analyses of regions with ivermectin distribution campaigns.

Therapeutic Advances: 

A large majority of randomized and observational controlled trials of ivermectin are reporting repeated, large magnitude improvements in clinical outcomes. Numerous prophylaxis trials demonstrate that regular ivermectin use leads to large reductions in transmission. Multiple, large “natural experiments” occurred in regions that initiated “ivermectin distribution” campaigns followed by tight, reproducible, temporally associated decreases in case counts and case fatality rates compared with nearby regions without such campaigns.

Conclusions: 

Meta-analyses based on 18 randomized controlled treatment trials of ivermectin in COVID-19 have found large, statistically significant reductions in mortality, time to clinical recovery, and time to viral clearance. Furthermore, results from numerous controlled prophylaxis trials report significantly reduced risks of contracting COVID-19 with the regular use of ivermectin. Finally, the many examples of ivermectin distribution campaigns leading to rapid population-wide decreases in morbidity and mortality indicate that an oral agent effective in all phases of COVID-19 has been identified.

https://journals.lww.com/americantherapeutics/Fulltext/2021/00000/Review_of_the_Emerging_Evidence_Demonstrating_the.4.aspx

SARS-CoV-2 Origin: Did Cell Culture Experiments Lead to Higher Virulence of Progenitor Virus in Humans?

 BERND KAINA

 DOI: https://doi.org/10.21873/invivo.12384

PDF: https://iv.iiarjournals.org/content/invivo/35/3/1313.full.pdf

Abstract

We are currently in a rapidly expanding pandemic of the SARS-CoV-2 virus, which originated in the city of Wuhan in central China. The disease COVID-19 is now spread worldwide and has tremendous socio-economic consequences. The origin of the virus can be reconstructed through epidemiological studies and, even more so, from genome comparisons. How the evolution of the virus and the transition to humans might have happened is the subject of much speculation. It is considered certain that the virus is of animal origin and very likely passed from bats to humans in a zoonotic event. An intermediate host was postulated, but many SARS-like bat viruses have the ability to infect human cells directly, which has been shown experimentally by scientists in the Wuhan Institute of Virology using collected specimens containing virus material from horseshoe bats. The propagation of SARS-like bat viruses in cell culture allowed experiments aimed at increasing the infectivity of the virus and adaptation to human cells. This article summarizes the unique properties of SARS-CoV-2 and focusses on a specific sequence encoding the spike protein. Possible scenarios of virus evolution are discussed, with particular emphasis on the hypothesis that the virus could have emerged unintentionally through routine culture or gain-of-function experiments in a laboratory, where it was optimally adapted to human cells and caused cryptic infections among workers who finally spread the virus causing the pandemic.

https://iv.iiarjournals.org/content/35/3/1313

Biotech Investors: Mark Your Calendar For May PDUFA Dates

 Following a mixed month in April, the Food and Drug Administration sets out to review another slate of drugs in May.

ACADIA Pharmaceuticals Inc.'s ACAD 0.15% Nuplazid failed to get label expansion to include the indication of dementia-related psychosis. The FDA did not keep its tryst with the decision dates for ACADIA Pharmaceuticals Inc.'s ACAD 0.15% pain drug and Sol-Gel Technologies Ltd.'s SLGL 2.67% investigational skin inflammation treatment.

Protalix BioTherapeutics, Inc.'s PLX 4.81% Fabry disease treatment candidate also faced rejection at the FDA altar. The regulatory agency extended the review period for Pfizer Inc.'s PFE 0.03% atopic dermatitis drug.

On the other hand, Supernus Pharmaceuticals, Inc.'s 

SUPN 2.62% attention deficit hyperactivity drug cleared the FDA hurdle in its second attempt. And GlaxoSmithKline plc's GSK 0.4% Jemperli, a new molecular entity, won the nod for advanced endometrial cancer.

Another the NMEs approved during the month was ADC Therapeutics SA's ADCT 4.12% Zynlonta in relapsed or refractory large B-cell lymphoma.

Here are the key FDA approvals scheduled for May:

Will Third Time Be Charm For Heron?

• Company: Heron Therapeutics, Inc. HRTX 0.79%
• Type of Application: NDA
• Candidate: HTX001
• Indication: postoperative pain
• Date: May 12

Heron's HTX-011, a non-opioid pain drug, is a combo drug consisting of bupivacaine and a low dose of non-steroidal anti-inflammatory drug meloxicam.

The NDA was originally submitted in October 2018, and in response to the application, the FDA issued a complete response letter in April 2019, citing the need for additional CMC and non-clinical information.

Heron resubmitted the NDA in October 2019, and in Feb. 2020, the company said the FDA extended the review period by three months, rendering the PDUFA data on June 26. A second complete response letter was handed out on June 29, with the FDA seeking additional non-clinical information.

The company went on to file a resubmission on Nov. 12. If approved, HTX-011 will compete with Pacira Biosciences Inc's PCRX 1.59% Exparel.

Apellis Awaits Nod For Blood Disorder Drug

• Company: Apellis Pharmaceuticals, Inc. APLS 5.04%
• Type of Application: NDA
• Candidate: pegcetacoplan
• Indication: paroxysmal nocturnal hemoglobinuria (PNH)
• Date: May 14

Pegcetacoplan is an investigational, targeted C3 therapy designed to regulate excessive activation of the complement cascade, a part of the body's immune system. The company is evaluating pegcetacoplan in several clinical studies across hematology, ophthalmology, nephrology and neurology.

PNH is a rare, chronic and life-threatening blood disorder characterized by the destruction of oxygen-carrying red blood cells through extravascular and intravascular hemolysis, or rupturing of red blood cells.

The FDA accepted the application for priority review on Nov. 16 and assigned a PDUFA goal date of May 14.

Can Sanofi's Enzyme Replacement Therapy For Pompe Disease Cross The FDA Hurdle?

• Company: Sanofi SNY 0.65%
• Type of Application: biologic license application
• Candidate: avalglucosidase alfa
• Indication: Pompe disease
• Date: May 18

Avalglucosidase alfa, an enzyme replacement therapy, is being evaluated for the treatment of patients with Pompe disease, a rare degenerative muscle disorder that can impact an individual's ability to move and breathe. It affects an estimated 3,500 people in the U.S. and can manifest at any age from infancy to late adulthood.

Bristol-Myers Squibb Seeks Label Expansion For Cancer Immunotherapy Opdivo

• Company: Bristol-Myers Squibb Company BMY 0.75%
• Type of Application: sBLA
• Candidate: Opdivo
• Indication: esophageal cancer
• Date: May 20

The pharma giant is seeking label expansion for Opdivo as a treatment option for patients with surgically removed esophageal or gastroesophageal junction cancer under certain circumstances.

The regulatory application was filed based on results from the CheckMate -577 trial. The FDA accepted the application for priority review on Jan. 20, assigning it a PDUFA goal date of May 20.

Related Link: Why This Bristol-Myers Squibb Stock Analyst Is Turning Bullish On The Pharma Company's Pipeline

No Or No-Go For Eton's Dehydrated Alcohol Injection

• Company: Eton Pharmaceuticals, Inc. ETON 0.23%
• Type of Application: Dehydrated alcohol injection
• Candidate: NDA
• Indication: methanol poisoning
• Date: May 27

The regulatory application for dehydrated alcohol injection was accepted for review in October 2020. Eton's application has an orphan drug designation for the treatment of methanol poisoning and is expected to receive seven years of market exclusivity upon its approval.

The U.S. market for dehydrated alcohol injection, according to Eton, is estimated to be greater than $100 million annually and the drug is currently only supplied by a single manufacturer.

Decision Due On Lantheus' Prostate Cancer Imaging Agent

• Company: Lantheus Holdings, Inc. LNTH 0.77%
• Type of Application: NDA
• Candidate: PyL
• Indication: prostate cancer
• Date: May 28

The FDA accepted the NDA for priority review in December. PyL is an investigational fluorinated PSMA-targeted PET imaging agent that enables visualization of localized prostate cancer as well as bone and soft tissue metastases to determine the presence or absence of recurrent and/or metastatic prostate cancer.

There is a significant unmet need for reliable, targeted imaging in prostate cancer, particularly in the high risk and biochemically recurrent populations, according to Lantheus.

Eton Eyes Epilepsy Drug Approval

• Company: Eton
• Type of Application: NDA
• Candidate: Zonisamide Oral Suspension
• Indication: epilepsy
• Date: May 29

The NDA for zonisamide oral suspension for the treatment of partial seizures in patients with epilepsy was accepted for review in October. Eton recently announced that it has sold its neurology portfolio, including lamotrigine, zonisamide and topiramate to privately-held Azurity Pharma for up to $45 million, including upfront and milestone payments.

Azurity will assume control of all three products and will be responsible for commercialization following regulatory approval. Eton will support Azurity in the transition and through regulatory approval. Eton will also receive a single-digit percentage royalty on Azurity's net sales of the products.

Bristol-Myers Squibb's Zeposia On Track For Second Nod?

• Company: Bristol-Myers Squibb
• Type of Application: sNDA
• Candidate: Zeposia
• Indication: ulcerative colitis
• Date: May 30

Zeposia is an oral drug, which was approved by the FDA for the treatment of adults with relapsing forms of multiple sclerosis in March 2020. Bristol-Myers Squibb is now looking to get FDA's approval to allow its usage as a treatment option for adults with moderately to severely active ulcerative colitis.

The company communicated FDA's acceptance of the sNDA on Feb. 1. Following the redemption of a Priority Review Voucher with the submission, the FDA has assigned a PDUFA goal date of May 30.

Will Roche's Esbriet Get The Nod For Another Lung Disease?

• Company: Roche Holding AG RHHBY 1.36%
• Type of Application: sNDA
• Candidate: Esbriet
• Indication: unclassified interstitial lung disease
• Date: May (expected)

Esbriet is an oral medicine approved for the treatment of a lung disease called idiopathic pulmonary fibrosis. Roche has filed the regulatory application for expanding the label to include the indication of unclassified interstitial lung disease.

ILD broadly describes a diverse group of more than 200 types of rare pulmonary diseases. These share similar features, including cough and shortness of breath.

The FDA accepted the sNDA for priority review on Jan. 21, with Roche stating that the decision is expected in May.

Adcom Reviews

FDA's Arthritis Advisory Committee is scheduled to meet on May 6 to discuss ChemoCentryx, Inc.'s CCXI 7.4% NDA for avacopan oral capsules, for the treatment of anti-neutrophil cytoplasmic antibody-associated vasculitis. The meeting is scheduled for between 10 a.m. and 4:15 p.m.

FDA's Endocrinologic and Metabolic Drugs Advisory Committee will meet on May 27 to discuss Provention Bio, Inc.'s PRVB 2.84% BLA for teplizumab intravenous infusion, for the delay or prevention of clinical type 1 diabetes mellitus in at-risk individuals. The regulatory agency warned of deficiencies in the regulatory application, deeming that the pharmacokinetic profiles of the company's candidate and Eli Lilly and Company's LLY 0.3% original drug substance used in the bridging study are not comparable.

https://www.benzinga.com/general/biotech/21/05/20890405/attention-biotech-investors-mark-your-calendar-for-may-pdufa-dates