Blair Starts Generation Bio (GBIO) at Outperform

 William Blair analyst Raju Prasad initiates coverage on Generation Bio (NASDAQ: GBIO) with a Outperform rating.

The analyst comments "Exploring the clinical potential of nonviral gene therapy. While AAV gene therapy has produced impressive clinical data to date, there are some notable drawbacks to this approach. These include: 1) the size of a transgene that can be used (less than 5 kilobases of genetic cargo); 2) potential for waning of durability of effect as evidenced in BioMarin’s Roctavian long-term data in hemophilia A; 3) nonoptimal transduction efficiency, which can result in the need for higher doses and subsequently require more manufacturing lots; and 4) immunogenicity, including both preexisting neutralizing antibodies against the AAV vector and increasing the need for prophylactic steroid use with initial delivery. Generation Bio’s technology value proposition is a redosable, titratable gene therapy that allows for a larger genetic payload, tissue specificity, and a capsid-free manufacturing process, with the potential to improve on both AAV gene therapy and biologic offerings."

https://www.streetinsider.com/Analyst+Comments/UPDATE%3A+William+Blair+Starts+Generation+Bio+%28GBIO%29+at+Outperform/18019436.html

Anavex Life Sciences (AVXL) PT Raised to 'Street High' at Cantor

 Analyst Charles Duncan raised his target to $25

https://www.streetinsider.com/Analyst+Comments/Anavex+Life+Sciences+%28AVXL%29+PT+Raised+to+Street+High+%2425+at+Cantor+Fitzgerald/18020535.html

Big Differences in Long-Term Immunity From Mild v. Severe COVID-19 Cases

 A big question on people’s minds these days: how long does immunity to SARS-CoV-2 last following infection?

Now a research team from La Jolla Institute for Immunology (LJI), The University of Liverpool and the University of Southampton has uncovered an interesting clue. Their new study suggests that people with severe COVID-19 cases may be left with more of the protective “memory” T cells needed to fight reinfection.

“The data from this study suggest people with severe COVID-19 cases may have stronger long-term immunity,” says study co-leader LJI Professor Pandurangan Vijayanand, M.D., Ph.D.

The research, published on January 21, 2021, in Science Immunology, is the first to describe the T cells that fight SARS-CoV-2 in “high resolution” detail.

“This study highlights the enormous variability in how human beings react to a viral challenge,” adds co-leader Christian H Ottensmeier, M.D., Ph.D., FRCP, a professor at the University of Liverpool and adjunct professor at LJI.

Since early in the COVID-19 pandemic, scientists at LJI have investigated which antibodies and T cells are important for fighting SARS-CoV-2. As experts in genomics, Vijayanand and Ottensmeier have used sequencing tools to uncover which T cell subsets may control disease severity. In October, the team published the first detailed look at how CD4+ T cells respond to the virus.

For the new study, the researchers used a technique called single-cell transcriptomics analysis to study the expression of individual genes of more than 80,000 CD8+ T cells isolated from both COVID-19 patients and non-exposed donors. CD8+ T cells are the cells responsible for destroying virus-infected host cells. “Memory” CD8+ T cells are also important for protecting the body from reinfection against many viruses.

The team studied CD8+ T cells from 39 COVID-19 patients and 10 subjects who had never been exposed to the virus (their blood samples were given before the pandemic). Of the COVID-19 patients, 17 patients had a milder case that did not require hospitalization, 13 had been hospitalized, and nine had needed additional ICU support.

To the researchers’ surprise, they saw weaker CD8+ T cell responses in patients with milder COVID-19 cases. The researchers saw the strongest CD8+ T cell responses in the severely ill patients who required hospitalization or ICU support.

“There is an inverse link between how poorly T cells work and how bad the infection is,” says Ottensmeier. “I think that was quite unexpected.”

One could expect to see a stronger CD8+ T cell response in the mild cases, since these are the cases where the immune system was equipped to fight off a severe infection — but the study showed the opposite. In fact, CD8+ T cells in the milder cases showed the molecular signs of a phenomenon called T cell “exhaustion.” In cases of T cell exhaustion, cells receive so much immune system stimulation during a viral attack that they are less effective in doing their jobs.

While more research is needed, Vijayanand and Ottensmeier think it is worth studying whether T cell exhaustion in the mild COVID-19 cases may hinder a person’s ability to build long-term immunity.

“People who have severe disease are likely to end up with a good number of memory cells,” says Vijayanand. “People with milder disease have memory cells, but they seem exhausted and dysfunctional — so they might not be effective for long enough.”

The new study provides a valuable window into CD8+ T cell responses, but it is limited because it relies on the CD8+ T cells found in blood samples. As a next step, the researchers hope to shed light on how T cells in tissues hit hardest by SARS-CoV-2, such as the lungs, react to the virus. This step will be important because the memory T cells that provide long-term immunity need to live in the tissues.

“This study is very much a first step in understanding the spectrum of immune responses against infectious agents,” says Ottensmeier. Going forward, the researchers hope to use single-cell sequencing techniques to look at CD8+ T cells in cancer patients with COVID-19 infection.

“This research highlights the power of these new tools to understand human immunology,” says Vijayanand.

Reference: “Severely ill COVID-19 patients display impaired exhaustion features in SARS-CoV-2-reactive CD8+ T cells” by Anthony Kusnadi, Ciro Ramírez-Suástegui, Vicente Fajardo, Serena J Chee, Benjamin J Meckiff, Hayley Simon, Emanuela Pelosi, Grégory Seumois, Ferhat Ay, Pandurangan Vijayanand and Christian H Ottensmeier, 21 January 2021, Science Immunology.
DOI: 10.1126/sciimmunol.abe4782

The study was supported by the National Institutes of Health (grants U19AI142742, U19AI118626, R01HL114093, R35-GM128938, S10RR027366, S10OD025052, the William K. Bowes Jr Foundation, the Whittaker Foundation, the Wessex Clinical Research Network and the National Institute of Health Research UK.

Additional study authors include co-first authors Anthony Kusnadi, Ciro Ramírez-Suástegui, Vicente Fajardo and Serena J Chee, as well as Benjamin J Meckiff, Hayley Simon, Emanuela Pelosi, Grégory Seumois and Ferhat Ay.

https://scitechdaily.com/big-differences-in-long-term-immunity-resulting-from-mild-vs-severe-covid-19-cases/

California coronavirus strain may be more infectious—and lethal

 A new strain of the pandemic coronavirus, first identified and now spreading in California, appears to be somewhat more transmissible and heighten patients’ risk of admission to the intensive care unit (ICU) and death, according to a preprint reporting lab studies and epidemiological data.

The variant is also present in other states, but its prevalence among more than 2000 samples collected in California swelled from 0% to greater than 50% between September 2020 and late January, according to researchers at the University of California, San Francisco (UCSF). “This variant is concerning because our data shows that it is more contagious, more likely to be associated with severe illness, and at least partially resistant to neutralizing antibodies,” says senior author Charles Chiu, an infectious diseases physician and sequencing expert at UCSF. The data suggest the new strain “should likely be designated a variant of concern warranting urgent follow-up investigation,” the authors write in their preprint, which has not been peer reviewed and which they say is expected to be posted online soon.

The findings “warrant taking a much closer look at this variant,” says Angela Rasmussen, a virologist at Georgetown University’s Center for Global Health Science and Security who was not involved with the research. They “underscore the importance of pulling out all the stops in terms of both exposure reduction and increased vaccine distribution and access.”

But other coronavirus experts say more data are needed before conclusions are drawn, noting that among patients with the variant, the study included fewer than 10 who were admitted to the ICU and fewer than 10 who died. “If I were a reviewer, I would want to see more data from more infected people to substantiate this very provocative claim,” says David O’Connor, a viral sequencing expert at the University of Wisconsin, Madison, who was not part of the research.

For their study, the authors sequenced 2172 genomes from virus samples captured from patients in 44 California counties between 1 September 2020 and 29 January. The new variant, which comes in two forms labeled B.1.427 and B.1.429 that carry slightly differing mutations, accounted for 21.3% of these sequences overall. (Under a different naming scheme, the variant is sometimes referred to as 20C/L452R.)

The scientists also studied the medical records of 324 people with COVID-19 who were cared for at UCSF clinics or its medical center. The researchers adjusted the data to account for differences in age, gender, and ethnicity, and found that, compared with patients who had other viral strains, those carrying the variant were 4.8 times more likely to be admitted to the ICU and more than 11 times more likely to die.

Other data suggest the variant is more contagious. The scientists found that people infected with the variant harbored about twice as much virus in their noses, an index of viral shedding, which may make them more infectious to others. In the lab, viruses engineered to carry a key mutation found in the variant were better than control viruses at infecting human cells and lunglike structures called organoids. And in one nursing home where the variant took hold, it spread severalfold faster than in four other nursing home outbreaks caused by other viral variants. “The evidence is growing that this [variant] is more transmissible than [its] immediate competitors,” although not as transmissible as some other variants of concern, says William Hanage, an expert on viral evolution at the Harvard T.H. Chan School of Public Health. (Variants of concern are coronaviruses with mutations that make them more likely to spread, evade vaccines, or make people sicker.)

In lab studies, B.1.429 also impacted the effectiveness of antibodies: It was four times less susceptible than the original coronavirus to neutralizing antibodies from the blood of people who recovered from COVID-19, and two times less susceptible to antibodies from the blood of people vaccinated with the Pfizer or Moderna vaccines. That diminished potency is “moderate but significant,” the researchers wrote.

Robert Schooley, an infectious disease physician and virologist at UC San Diego, praised the paper’s ambition and noted its findings of high viral loads in infected people’s noses. “The biology of having a higher level of virus … would certainly fit the thesis that people would not do as well,” he says. That comports with the fact that “we are seeing here in Southern California more people … for a longer period of time in our ICUs.”

The patient data suggest the variants may be linked to worse outcomes. But although the ICU and mortality findings reached statistical significance, the numbers were small: Eight of 61, or 13%, of hospitalized patients with the variants were admitted to the ICU, compared with seven of 244, or 2.9%, of hospitalized patients who did not harbor the variants. Seven of 62 people (or 11.3%) with the variants died, versus five of 246 (or 2%) of people without the variants.

The authors admit it is not possible to tell whether the variants actually make people sicker or whether, for instance, most of the patients with the variant got sick during the worst months of the pandemic, when health care systems were overloaded and patient care may have been suboptimal. All the variant-infected patients in the study who died at UCSF did so between 22 December 2020 and 28 January, when the area was experiencing a surge of infections.

“Could any of the seven individuals who died with this variant have survived if they received treatment when the state wasn’t in the midst of a surge?” O’Connor asks. “It’s really impossible to know, as the authors acknowledge.”

The real evidence will be seeing if, when introduced elsewhere, these lineages start to take off in similar fashion.

William Hanage, Harvard T.H. Chan school of Public Health

In addition to other mutations, B.1.427 and B.1.429 each have an identical trio of mutations in the coronavirus spike protein, which allows the virus to invade human cells. One of those mutations, dubbed L452R, is thought to stabilize the interaction between the spike protein and the receptor it uses to attach to and invade human cells, increasing infectivity. None of those three spike mutations is found in the three other variants of concern, which emerged in the United Kingdom, South Africa, and Brazil.

Evolutionary biologists also caution against overinterpreting the study. “The work is definitely worth reporting, but I don’t buy that on its own this is sufficient to categorize these as variants of concern,” Hanage says. He notes that B.1.427 and B.1.429 likely emerged in July and June 2020, respectively, but infections have not exploded in the exponential curves seen with the three identified variants of concern. “The real evidence will be seeing if, when introduced elsewhere, these lineages start to take off in similar fashion.”

The paper also offers another cautionary tale about the United States’s subpar effort to sequence coronavirus samples nationwide. It’s “worrisome” that a state like Nevada, which borders California, has fewer than 500 sequences in GISAID, the leading coronavirus sequence repository, O’Connor says. The limited data from Nevada currently suggest the variant represents 27% of collected sequences, according to a database created by Scripps Research using GISAID data. 

https://www.sciencemag.org/news/2021/02/coronavirus-strain-first-identified-california-may-be-more-infectious-and-cause-more

India says virus variants not behind upsurge in cases

 India said on Tuesday mutated versions of coronavirus were not responsible for an upsurge in cases in two states, a potential relief for a country where mask-wearing and social distancing have largely disappeared.

Maharashtra in the west and Kerala in the south account for 75% of India’s current active cases of about 147,000, and both states have seen a sudden rise in new infections in recent days, fuelling calls for a faster roll-out of vaccines.

India has reported more than 11 million cases - the most in the world after the United States - and about 156,000 deaths. Actual infections have inched closer to 300 million in the country of 1.35 billion, according to a random study of antibodies done by the government.

A top government health official confirmed the long-time presence of two mutants - N440K and E484Q - in those two states as well as elsewhere in the country and abroad. Authorities have also found the UK variant in 187 people in India, the South African one in six and one case of the Brazilian mutation.

“There is no reason today for us to believe, on the basis of scientific information, that these are responsible for the upsurge of the outbreak,” Vinod Kumar Paul, who heads a government committee on vaccines, told a news conference.

Though cases have come down sharply since a September peak, Paul said India was still vulnerable, especially given that even previously badly affected cities like Pune in Maharashtra were getting hit again. He urged people to wear masks and avoid social events - guidelines openly flouted by both federal and state ministers.

The northern state of Punjab, which has also seen a rise in cases, said indoor gatherings would be restricted to 100 and outdoor to 200 from March 1. District heads have also been permitted to decide on night curfews in hotspots, and testing will be increased, the state’s chief minister said.

Punjab is one of the worst performing states in vaccinating their healthcare workers, according to the federal government.

The government on Tuesday asked five states, including Maharashtra and Punjab, to expedite vaccination of their healthcare and frontline workers in light of the surge in cases, according to letters shared by the health ministry.

India has given nearly 12 million doses to its health and frontline workers since beginning the campaign in mid-January, a pace that will have to be increased sharply to meet the target of reaching 300 million people by August.

Health Secretary Rajesh Bhushan said India would very soon start immunising people over 50 and those with medical conditions, with greater involvement from private hospitals. Government hospitals are now running around 80% of vaccination sites.

The government has recently come under pressure to expand coverage at home given the world’s largest vaccine maker has exported COVID-19 shots to more than two dozen countries.

India is using a vaccine developed by Bharat Biotech and the state-run Indian Council of Medical Research, and another licensed from AstraZeneca and Oxford University. Other vaccines are in the queue, including Russia’s Sputnik V and products from Cadila Healthcare and Novavax.

https://www.reuters.com/article/us-health-coronavirus-india-cases/india-says-virus-variants-not-behind-upsurge-in-cases-idUSKBN2AN16I

COVID-19 vaccine makers tell Congress U.S. supply will surge soon

 COVID-19 vaccine makers told Congress on Tuesday that U.S. supplies should surge in the coming weeks due to manufacturing expansions and new vaccine authorizations.

Executives from Pfizer Inc, Moderna Inc and Johnson & Johnson - speaking at a hearing at the U.S. House of Representatives - said they would be able to supply enough vaccine to have fully inoculated 130 million people in the United States by the end of March.

The drugmakers also reaffirmed their commitments to supply more than enough doses necessary to vaccinate all Americans by the end of July.

Pfizer Chief Business Officer John Young said it was plausible that there could be a surplus of vaccine in the United States sometime in the second quarter of this year.

“We certainly hope that we’re going to be in a position where every eligible adult will be able to receive vaccinations,” Young said.

Around 44.5 million people in the United States had received at least one dose of two-shot vaccines developed by Pfizer and BioNTech or Moderna, as of Tuesday morning.

U.S. President Joe Biden’s administration is trying to accelerate an unprecedented campaign to vaccinate most American adults, as local governments clamor for more doses and the virus kills thousands of Americans every day.

Demand for vaccines still far outpaces supply, but Pfizer and Moderna said their supply will soon rise sharply.

Pfizer expects to deliver more than 13 million doses of vaccine per week to the United States by the middle of March, up from 4 million to 5 million doses a week at the beginning of February. Moderna said it delivered 9 million doses last week and expects to soon be able to supply nearly 50 million doses a month.

Johnson & Johnson’s single-dose vaccine will be reviewed by an outside advisory committee to the U.S. Food and Drug Administration later this week, and emergency use authorization could come shortly afterward.

Richard Nettles, vice president of medical affairs at J&J’s Janssen Pharmaceuticals unit, said the company would be able to ship nearly 4 million doses of its COVID-19 vaccine upon authorization and 20 million doses by the end of March.

Additional vaccine supplies could also come from AstraZeneca Plc and from Novavax Inc, which are currently running clinical trials of their experimental shots.

An AstraZeneca executive said the drugmaker could supply doses necessary to vaccinate another 25 million people by the end of April if their vaccine is authorized by U.S. regulators.

Novavax said if its vaccine is authorized, it will be able to supply the United States with 110 million doses - enough to vaccinate 55 million people - by the third quarter of the year.

U.S. vaccination sites initially struggled to administer shots fast enough to keep pace with vaccine deliveries. More recently, however, supply constraints have slowed ambitious vaccination programs, as massive sites capable of putting shots into thousands of arms daily, as well as hospitals and pharmacies, beg for more doses.

CVS Health Corp Chief Executive Karen Lynch said on Tuesday the company would begin administering COVID-19 vaccines at its pharmacies across 17 states by end of this week.

It is currently vaccinating people at its pharmacies in 11 states in addition to several long-term care facilities, as part of a collaboration with the U.S. government.

https://www.reuters.com/article/us-health-coronavirus-usa-vaccines/covid-19-vaccine-makers-tell-congress-u-s-supply-will-surge-soon-idUSKBN2AN26R

New CDC school opening guidelines fail to ‘follow the science’

 President Biden vowed to “follow the science” in an effort to get kids back to school. But that’s not what the latest school opening guidelines from the Centers for Disease Control and Prevention do.

The two core pillars of the guidelines — that schools should decide whether to open based on community transmission and that students should strive to be spaced 6 feet apart — aren’t supported by science.

While there are many prudent recommendations in the document, these two demands will keep schools closed much longer than necessary, harming kids.

Should learning mode depend on community transmission levels?

The new school opening guidelines advise schools to open or close (or operate in “hybrid” mode) based on a four-tier color-coded system. Each color is tied to the number of new Covid-19 cases during the previous week. The red, or most restrictive category, is more than 100 cases a week per 100,000 people. By this metric, more than 90% of the country is currently in the most restrictive tier, ruling out full-time, in-person learning for elementary-aged students and any sort of in-person school for older children without screening tests.

Yet many schools in such communities already have in-person school — and have done so for months — without issue.

To justify this tiered approach, the CDC guidelines cite a “likely association” between community transmission levels and the risk of exposure in the schools. But the evidence for this is flimsy.

The CDC relies almost exclusively on a U.K. study that examined Covid-19 cases and outbreaks — defined as two or more linked cases — in educational settings in England during June and July. The CDC summarizes the study by noting: “For every 5 additional cases per 100,000 population in regional incidence, the risk of a school outbreak increased by 72%.”

While technically true, that increases is the relative risk, which obscures the study’s key finding about absolute risk: School outbreaks were vanishingly rare in this study —just 0.02% among schools that were open daily during this period — even in areas with high rates of community transmission. And if the CDC had looked at the next figure in the article, focusing on individual infections rather than outbreaks, no association was seen between the number of single infections in school and broader rates of community spread.

The CDC’s school opening guidelines also ignore the experience of at least two U.S. states. Schools in North Carolina and Wisconsin were open during periods of high community transmission (red zone), and both saw far fewer cases in schools than outside of them. The Wisconsin study was published in Morbidity and Mortality Weekly Report, the CDC’s own journal. If the state had taken the CDC’s advice, it never would have done the study in the first place. Moreover, if there is less viral spread in schools than in the community, we want them open precisely during periods of high community spread, when the comparative risks outside of school are highest.

Do schools drive the spread of Covid-19 in the larger community? The CDC guidelines cites two studies. One, using national data, found no overall increase in hospitalization in counties where schools opened this fall, relative to trends during the same period in areas where schools remained closed. For counties with the highest rates of Covid-19 spread when schools reopened, some estimates showed an increase in Covid-19 hospitalizations, but these effects were quite modest, on the order of 2% to 3% above baseline levels of hospitalization. Even if this difference is real, it is quite small and unlikely to overwhelm the health care system unless it is already at the breaking point.

A second study, focused on Michigan and Washington, suggested that schools can contribute to transmission when exiting case counts are high. But this analysis was vulnerable to a classic research problem of reverse causality: school reopening may have led to more frequent testing and detection of infections that would have otherwise gone unrecorded.

Put together, the available evidence offers little reason to believe that in-person learning is particularly risky to students, educators, or people in the community. We believe the benefits of school far outweigh these concerns, and this is especially true as vulnerable people get vaccinated.

Is 6-foot distancing really required?

The CDC guidelines say that schools should try to keep kids 6 feet apart. This guidance, however, appears to be based on decades-old research on the travel distance of large respiratory droplets.

The insistence on 6 feet was controversial from the start. One of the early skeptics was physician Rochelle Walensky, who was recently appointed to lead the CDC. She advised her local school district last summer that “it is quite safe and much more practical to be at 3 feet” as long as everyone is masked. (Three feet of distancing is also recommended by the World Health Organization.)

When asked to explain this about-face during a recent interview with CNN, Walensky argued that the larger distance in the CDC guidance was justified by new research published since last summer and the increase in case counts since then.

The newest evidence actually seems to argue against requiring strict adherence to a 6-foot rule, however. First, it is increasingly clear that transmission of Covid-19 is not explained by the droplet model — the idea that bigger drops of secretion fall in the first few feet around someone, as was thought when the original social distancing guidelines developed. Second, a meta-analysis on Covid-19 and other closely related coronaviruses showed that the benefits of increasing the distance from 3 to 6 feet is marginal in contexts where the risk of infection is low, as would be the case in a classroom with universal masking.

Most on point is a recent study that examined the dynamics of in-school transmission in Ohio. Working with seven school districts that offered in-person learning in late November and early December of last year, near the peak of daily recorded infections in the state, researchers identified all students and teachers who had tested positive. They then repeatedly tested both their close contacts — other students who were exposed for more than 15 minutes at a distance of less than 6 feet — as well as a comparison set of students who kept their distance, including several hundred attending other classes within the same school. The rates of infection among close contacts and students who stayed more than 6 feet away were nearly identical in both elementary and high schools, suggesting minimal value from strict adherence to a 6-foot distancing rule as long as masks are worn consistently and correctly.

Three feet versus 6 might sound trivial, but it really matters. Given the limitation of classroom size, maintaining 6 feet of distance will thwart many schools from operating at full capacity, meaning that students would be able to attend part-time at best, using a hybrid model.

This requirement also complicates transportation. Although the main CDC guidance does not discuss transportation in detail, an accompanying handout advises districts to “skip a row if possible” on school buses. The busing constraint is particularly binding in large urban districts, where many students attend charter or magnet schools far away from their homes and rely on district-provided transportation.

Going backward on reopening

Rather than moving the ball forward on Biden’s goal of getting elementary and middle schools reopened as soon as possible, the new CDC guidelines will work to provide political cover for interest groups and districts that want to delay in-person school.

They also come when many states were acting to loosen their own guidelines to encourage schools to reopen. Just days before the CDC announcement, the state of Massachusetts announced the elimination of school bus capacity limits as long as bus windows remain open at least 2 inches. Nevada, which already allowed closer spacing on school buses, also loosened its requirements further. But, the new CDC guidelines would thwart these pragmatic efforts. The conflicting CDC guidance only creates confusion, putting districts in the difficult position of deciding whether to follow state or federal recommendations.

Most worrisome is that the stringent CDC criteria will likely increase pressure to reduce in-person learning in many places that have been operating at full capacity and with older students. As recent test score data from Ohio show, moving from in-person to hybrid formats will exacerbate learning losses, compounding the both the social and academic harms students have already experienced during the pandemic.

A truly science-based analysis must recognize the difficult tradeoffs involved — including the long-term of interests of children who are most directly affected — and carefully weigh modest increases in Covid-19 infection risk to educators and broader community members against the harms of school closures.

By promoting slavish adherence to arbitrary benchmarks and distancing requirements, the new CDC school opening guidelines do a disservice to science and kids.

Vladimir Kogan is an associate professor of political science at the Ohio State University. Vinay Prasad is a hematologist-oncologist and associate professor of medicine at the University of California, San Francisco.

https://www.statnews.com/2021/02/20/new-cdc-school-opening-guidelines-dont-follow-the-science/