Over-18s will be offered booster shot

Over-18s will be offered booster shot

As the FDA gets ready to approve boosters in all over-18s (for Pfizer/Moderna), the share of the population having received a first shot stands at 81% in Spain, 79% in Canada, 78% in Japan, 77% in Italy, 76% in Brazil and France, 75% in Australia, 74% in the UK, 69% in Germany, 66% in the US, 53% in India, and 40% in Russia. The daily pace of new doses administered (7DMA) increased to 8mn in China and decreased to 27mn globally, 0.8mn in the US, 0.8mn in the EU, and 2.9mn in India. The share of the population having received a booster shot stands at 45% in Israel, 33% in Chile, 15% in Turkey and the UK, 13% in Singapore, 7% in the US, 5% in Brazil and France, 4% in Thailand and Italy, 3% in Germany and Spain, 2% in Canada, and 1% in Russia and Malaysia. Over the past week virus outbreaks have worsened in Germany, Norway, the Czech Republic, New Zealand, Vietnam, Poland, South Korea, and Russia and improved in Romania, Singapore, Australia, and the UK (see chart). In developed markets, virus spread decreased in the UK and Canada, remained low in Japan and Spain, moderated in the US, increased in France and Italy, and surged in Germany:

In the UK we often ask how bad the winter could get with regard to COVID-19 infections and what is the likelihood of a return to broad-based lockdown measures? JPM’s answer is that infections, hospitalizations and deaths in the UK are all likely to remain high, or even rise further, in the coming months but not by enough to push the country back into a broad-based lockdown. Instead, there will be a number of intermediate steps taken to control the situation, if needed: an increase in the main vaccination and booster programs; a return to mandatory mask wearing in public spaces; an encouragement to work from home where possible; and the introduction of a vaccine certificate regime. In addition, individual behaviour will likely turn more cautious if infections rise. Only if all of these steps failed to control infections would the government return to broad-based controls on movement and mixing. They also expect the intermediate steps to be successful, if needed. Their analysis suggests that the booster program could pretty much exactly offset the impact of fading vaccine protection. They also look at the analysis from Imperial College, who recently published their scenarios for the winter. Only if everything goes wrong can Imperial College envisage a situation where the pressure on the healthcare system becomes serious enough to prompt a return to broad-based lockdown measures.

Looking at the outlook through the lens of the effective reproduction number: JPM have already laid out a framework for considering the interaction of fading vaccine protection and booster jabs. They assume that vaccine protection against infection moves in line with academic estimates, with continued declines in protection as time after the second dose passes (Table 1). They also assume that second dose vaccinations continue at a daily pace of 30,000 and that booster jabs continue at a daily pace of 300,000. Although the UK booster program got off to a slow start, the pace is now very high. During October, 8.1 million individuals received a booster jab, and over the past week boosters have averaged a daily pace of 302,000.

Table 2 lays out the implications of these assumptions for pressure on the effective reproduction number (Re). The first column shows the downward pressure on Re assuming that vaccine protection against infection holds steady at 78%. By next March, if the basic reproduction number (R0) of the Delta variant is 4.5, then the vaccinations alone would push the Re to 1.92 (4.50 minus 2.58). Infections are only stable (Re=1) if acquired immunity from prior infection and recovery and some cautious individual behaviour also exert downward pressure on Re. Thus, even without any fading of vaccine protection, the main two-dose vaccination program is not sufficient on its own to stabilize infections given the impact of the Delta variant on R0.

The second column of Table 2 shows the impact of fading vaccine protection assuming no booster program. Essentially, the downward pressure on Re starts to moderate from October, at an average monthly pace of 0.10. This means that after six months, all else equal, Re would be 0.6 higher than otherwise. This is a significant increase. A move in Re from 1.0 to 1.6 would mean that infections would go from a situation where they are stable to a situation where they are doubling every 8 days. The final column of Table 2 shows the impact of a booster program comprising 300,000 jabs a day. Essentially, the assumed booster program more than offsets the impact of fading vaccine efficacy, so that the downward pressure on Re continues beyond October, albeit at a very modest pace. This suggest that even with a slightly more moderate booster program than assumed, Re could remain close to one over the winter. This would imply a relatively stable daily pace of infections, hospital admissions and deaths at close to the recent level. A situation like this would not prompt any broad-based lockdown measures.

Imperial College’s assessment of the outlook: Imperial College has just published twelve scenarios for the period 8 October 2021 to 31 March 2022, which vary according to the assumptions made about immunity, boosters and mobility. Table 3 describes the key assumptions made by Imperial College. Table 4 lays out four of their scenarios. The most optimistic scenario envisages daily infections averaging 27,600 over this period (cumulative infections of 4,831,400 divided by 175 days). This is lower than the recent daily pace of around 35,400. This scenario does not envisage any pressure on the healthcare system. Indeed, according to this scenario we have already passed the peak in hospital occupancy, which currently stands at around 9,160.

Imperial lays out a pessimistic scenario but one which still includes a booster program. In this scenario, daily infections average 73,000 (12,772,600 divided by 175) between 8 October 2021 and 31 March 2022. The pressure on the healthcare system is modest in this scenario. Hospital occupancy is only up slightly relative to the level of 6,800 seen on 8 October, which was the last observation when the projections were made. Only if Imperial College takes the pessimistic assumptions and assumes no booster program can it generate the kind of pressure on the healthcare system that would prompt a broad-based lockdown. In the final scenario on Table 4, daily infections average 99,500 (17,406,900 divided by 175) between 8 October 2021 and 31 March 2022. In this scenario, hospital occupancy is expected to reach 36,000 in January next year, not far short of the all-time peak of 39,000 reached in January 2021.

Given the non-linear nature of viral dynamics, outcomes are very sensitive to initial conditions and assumptions made. On the one hand, things could be better than Imperial College envisages. They assume no changes in behavior, whether driven by individual concerns or government mandates, which would likely come in stages if the healthcare system came under pressure. On the other hand, things could be worse than Imperial College envisages. They assume no new variants and do not incorporate pressure coming on the healthcare system from other respiratory illnesses. But, nevertheless, the overall message seems clear. According to Imperial College, lot of things have to go wrong to see a return to a broad-based lockdown in the UK.

Of course, there is plenty of uncertainty about what the winter may bring. But, having looked at the situation from a couple of different perspectives, we are comfortable arguing that a return to broad-based restrictions on mobility and mixing is very unlikely. Although vaccine protection against infection fades fairly quickly, vaccine protection against serious illness and death seems to hold up much better. Thus, a much higher level of infections can be tolerated before restrictions need to be imposed.

Table 1: Assumptions on vaccine protection against infection

Months after second dose

Vaccine efficacy (%)

1

78

2

78

3

70

4

63

5

59

6

54

7

49

8

44

9

39

10

34

11

29

12

24

   
   

 

Table 2: Impact of vaccinations on the effective reproduction number

 

No fading of protection

Fading of protection with no boosters

Fading of protection with boosters

March 2021

-0.11

-0.11

-0.11

April 2021

-0.48

-0.48

-0.48

May 2021

-1.05

-1.04

-1.04

June 2021

-1.55

-1.49

-1.49

July 2021

-1.84

-1.68

-1.68

August 2021

-2.10

-1.81

-1.81

September 2021

-2.27

-1.85

-1.85

October 2021

-2.35

-1.79

-1.90

November 2021

-2.40

-1.68

-1.94

December 2021

-2.44

-1.57

-1.97

January 2022

-2.49

-1.46

-2.01

February 2022

-2.53

-1.35

-2.06

March 2022

-2.58

-1.23

-2.10

 
       
         

 

 

Table 3: Assumptions underlying Imperial College scenarios

 

Central scenario

Pessimistic scenario

Mobility from 1 December 2021

20% below pre-pandemic level

At pre-pandemic level

Vaccine efficacy against infection %

   

Initial after 2nd dose

72

62

20 weeks after 2nd dose

55

48

After booster

92

78

Main vaccination program 2nd doses daily

28,600

28,600

Booster program doses daily

186,000

186,000

Cross-protection from earlier infection %

85

75

 
     

 

Table 4: Imperial College scenarios for the winter

Cumulative figures for 8 October 2021 to 31 March 2022

 

Infections

Hospital admissions

Deaths

Peak hospital admissions

Central scenario with boosters

4,831,400

42,800

5,300

5,000

Central scenario with no boosters

6,924,800

150,900

21,700

8,000

Pessimistic scenario with boosters

12,772,600

100,300

9,900

7,500

Pessimistic scenario with no boosters

17,406,900

418,200

59,900

36,000

 
         
             

 

 

Table 5: Imperial College scenarios for the winter

Average daily pace for 8 October 2021 to 31 March 2022

 

Infections

Hospital admissions

Deaths

Central scenario with boosters

27,600

245

30

Central scenario with no boosters

39,600

862

124

Pessimistic scenario with boosters

73,000

573

57

Pessimistic scenario with no boosters

99,500

2,390

342

Peak in January 2021

68,053

4,583

1,244

Average of past 7 days

35,400

1,034

129

 

There’s always orals. And we just heard that Regeneron’s antibody protects for 2-8 months too by 81.6%. Following Friday readout of Pfizer’s Paxlovid (oral PI for treating COVID-19) in high-risk patients (Phase 2/3 EPIC-HR study), many see these data as a game-changer given the magnitude of benefit (89% reduction in hospitalization or death, 100% reduction in death) seen in high-risk patients. At the same time, I am not viewing this as necessarily a winner-take-all market (although we clearly anticipate Paxlovid to represent the go-to product in the space) and still anticipate fairly significant molnupiravir sales (at least in the near term) for Merck. Additional readouts in standard risk and prophylaxis populations could represent meaningful upside to this estimate and we see a fairly high likelihood of success for those studies in the light of Friday’s best-case scenario data. This outlook assumes adequate Paxlovid manufacturing capacity (which appears to be the case with Pfizer suggesting up to 50mm courses of the drug by year-end 2022). Many expect substantial government stocking of both agents over the next 12-24 months given still elevated hospitalization levels as well as the unpredictable nature of how the pandemic has evolved. Longer-term, many assume some residual sales, particularly for Paxlovid, even as the pandemic recedes, similar to what was historically seen with Tamiflu. In an upside scenario, most assume a broader addressable population for Paxlovid including potential use in standard risk and prophylaxis populations where clinical studies are ongoing with expected readouts early next year. For Merck, while shares sold off meaningfully on Friday on the back of positive Paxlovid study results, there is still a significant near-term opportunity with the company highlighting expectations for $5-7bn in molnupiravir sales through YE2022 based on existing contracts in place and additional contracts with clear line of sight. Importantly, Merck’s forecast already assumed competition in the antiviral market and does not include any sales in the prophylaxis setting where the company still has an ongoing study (MOVe-AHEAD phase 3). While Paxlovid clearly appears to have an efficacy advantage over molnupiravir (acknowledging very different placebo hospitalization rates which imply a sicker population for Merck’s drug), I do not anticipate governments make a definitive choice for one drug over the other in the near-term and expect most to stockpile both products.

What’s next for the COVID antivirals? We are watch ongoing standard risk and prophylaxis studies as well as EUA approvals. For Paxlovid, Pfizer is currently running two additional studies for standard risk treatment (EPIC-SR, 1Q22), and post-exposure prevention (EPIC-PEP, 1Q22/2Q22) which could both represent opportunities that meaningfully expand the product's addressable patient population. Based on the high primary effect size and viral load reduction seen in the Phase 2/3 EIC-HR study for high-risk non-hospitalized patients, Pfizer is very optimistic on the potential for these studies, and we see these as fairly high probability readouts following Friday’s data. Pfizer currently plans to submit data for high-risk setting by Nov 25 to the US FDA for EUA approval as soon as possible. For molnupiravir, Merck currently has an ongoing Phase 3 study for post-exposure prophylaxis to prevent the spread of COVID-19 in households which could further expand the role of the product. In the high-risk setting, Merck has filing for EUA approval with the FDA with upcoming advisory committee later this month (Nov 30) and ultimate approval expected later this year. Outside the US, Merck is engaging regulators globally including the product first approval in the UK last week.

Figure 1: Paxlovid (protease inhibitor + ritonavir) Study Program

 

COVD-19 vaccination remains the key first-line defence for the ongoing pandemic with high vaccination rates showing a demonstrated benefit of lower incidence rates, reduction in transmission, and significantly lower hospitalization and death. At the same time, the introduction of highly effective therapeutic options could have some negative impact on vaccination rates over time, particularly the booster shot eligible population who have already received their primary vaccination series as well as those who have been hesitant to be vaccinated.

Both Paxlovid (~89% risk reduction) and molnupiravir (~50% risk reduction) demonstrated significantly lower risk of hospitalization and/or death in high risk, non-hospitalized patients. For Paxlovid, the phase 2/3 EIC-HR study of Paxlovid (protease inhibitor + ritonavir) showed an ~89% reduction the risk of hospitalization and/or death (primary endpoint for the study) with hazard ratio comparing favourably to the ~50% reduction the risk of hospitalization and/or death for molnupiravir in the Phase 3 MOVe-OUT study. Importantly, both products showed a 100% reduction in death with no patients dying in the active study arms as well as a highly tolerable safety profile with fewer incidence of AEs and discontinuation relative to placebo. Looking to the relative positioning of the two products, I see Pfizer's Paxlovid with the advantage based on current data sets with the product showing higher effect size on hospitalization and high viral load reduction. At the same time, I note typical challenges with cross-trial comparisons and differences in study design which includes: i) significantly higher proportion of patients hospitalized in the placebo of Merck's molnupiravir study (i.e. sicker patient population) as well as, ii) differences in access to alternative therapies including COVID antibody therapies.

The placebo point mentioned above is important. In addition, while Pfizer's topline data appears to be significantly better (89% vs. molnupiravir's 50% in reduction of hospitalization or death), the populations are different (7% placebo hospitalization rate in the Pfizer's study vs. 14% in the Merck's study) which makes the comparison more difficult.

But, William Haseltine, a virologist formerly at Harvard University known for his work on HIV and the human genome project, suggests that by inducing viral mutations, molnupiravir could spur the rise of new viral variants more dangerous than today’s. “You are putting a drug into circulation that is a potent mutagen at a time when we are deeply concerned about new variants,” says Haseltine, who outlined his concern in a blog post in Forbes. “I can’t imagine doing anything more dangerous”:

https://www.forbes.com/sites/williamhaseltine/2021/11/01/supercharging-new-viral-variants-the-dangers-of-molnupiravir-part-1/?sh=56304aab6b15

He notes that patients who are prescribed antibiotics and other drugs often don’t complete a prescribed medication course, a practice that can allow resistant germs to survive and spread. If COVID-19 patients feel better after a couple of days and stop taking molnupiravir, Haseltine worries viral mutants will survive and possibly spread to others. “If I were trying to create a new and more dangerous virus in humans, I would feed a sub-clinical dose [of molnupiravir] to people infected,” Haseltine says. “The possibility [of generating variants] is there,” agrees Raymond Schinazi, an infectious disease expert at Emory University. Katzourakis says, “I don’t share the alarm in this. If you force an organism to mutate more, it’s more likely to be bad for the virus.”

Underpinning Haseltine’s worry are studies that show coronaviruses can survive with molnupiravir-induced mutations. Two years ago, for example, Mark Denison, a virologist at Vanderbilt University, and colleagues repeatedly exposed coronaviruses to sublethal doses of a drug EIDD-1931 to test whether drug-resistant viruses would emerge. They reported that in populations of two coronaviruses—murine hepatitis virus and the virus that causes Middle East respiratory syndrome--30 rounds of such drug treatment caused up to 162 different mutations that did not kill the viruses. But Denison notes that his study didn’t catalogue mutations in individual viruses; rather, up to 162 mutations arose in populations of cells infected with one of the two coronaviruses:

https://journals.asm.org/doi/10.1128/JVI.01348-19

Most of the mutations harmed the virus, slowing growth. “If I take away anything from our work, it is that if the virus tries to adapt, say through resistance [to molnupiravir], it continuously develops deleterious mutations,” Denison says. However, Ravindra Gupta, a microbiologist at the University of Cambridge, cautions that mutated viruses may have better odds of flourishing in the people most likely to take molnupiravir: patients with compromised immune systems. Because vaccines are less effective at protecting those patients, he says, “these are precisely the people who are most likely to receive [molnupiravir].” Daria Hazuda, who heads infectious disease discovery for Merck, notes that the company hasn’t seen any evidence that people who take molnupiravir are generating viruses with new and dangerous mutations. In patients who completed the 5-day course of the drug, Hazuda says, “we don’t see any infectious virus”—let alone mutated variants. The mutations that arise along the way have been random, she says—not concentrated in a particular gene that would make the virus more likely to survive. “There is no evidence for any selective bias,” she says.

What’s more, Hazuda and others note, SARS-CoV-2 is plenty good at churning out variants naturally as it replicates in infected people. “There is no shortage of viral variation out there,” Katzourakis says. The more important question is whether molnupiravir provides selective pressure that drives the virus toward transmissibility or virulence. “I find it difficult to imagine,” he says. “But I can’t rule that out.” More likely, say Denison and others, is that use of molnupiravir will drive the emergence of virus that is no more deadly or transmissible but is resistant to the drug, a common outcome for anti-infectious agents. But Friday’s news that another antiviral drug, from Pfizer, is highly effective suggests a way to forestall resistance: using both pills in combination, the same multiprong strategy used to treat HIV and other infections. On 30 November, an FDA advisory committee will review possible emergency use authorization for molnupiravir in the United States.

We may never know the origin of Covid-19. The lack of hard facts precludes certainty and the knowledge gaps will probably not now be filled. More outlandish theories, such as the suggestion that the Chinese government created and released SARS-CoV-2 as a germ warfare weapon; or that the virus originated in the USA and reached China via infected US athletes and contaminated Maine lobsters (google it) can be discounted. The debate is between the natural-origin and lab-leak theories, and it is becoming increasingly sterile and ever-more vicious. There appear to be two major drivers behind this debate: One is assigning blame for what happened in late 2019. The other is preventing future pandemics by applying lessons learned. I believe that the second of these has more value than the first.

Finger pointing is a natural human trait. Finding and punishing the guilty can be important, even if only psychologically. But applying such motivations to the lab-leak theory long ago degenerated into China bashing and bizarre attacks on the National Institutes of Health and, more specifically, its highly public representative, Dr. Anthony Fauci. The Trump administration saw political advantage during 2020 in blaming China for an event that derailed Trump’s electoral prospects. The lab-leak theory was a useful way to deflect public attention away from the grossly inadequate American response to the spreading pandemic. The NIH and Fauci soon became targets for Republican venom, because a grant from the NIAID transferred money to the Wuhan Institute of Virology for research on bat viruses with the potential to infect humans.

The ongoing rhetoric from Republican politicians about the origin of Covid-19 accomplishes nothing other than further polarising U.S. society. The available public records show that the work done at the Wuhan Institute of Virology using U.S. government funds could not have created this virus but it may have been released by accident, The most recent lab-leak related controversy has centred on grant related paperwork violations. The scientific community has also been riven by unpleasant disputes. Allegations have been made that lab-leak opponents must have conflicts of interest, however nebulous. One positive outcome is that lab-leak theory has refocused the world’s virologists on an important scientific topic: gain of function research.

This work involves the experimental manipulation of a pathogen, most commonly a virus, in ways that increase its capacity to infect and/or spread among people. Because of the obvious risks to humanity, it is or should be tightly regulated. The virology community’s debate over gain-of-function research started a decade ago and involved dangerous influenza viruses like H5N1. It resurfaced last year when as-yet unproven allegations arose that some of the work on bat coronaviruses at the Wuhan Institute of Virology was related to gain of function and not always conducted under appropriate safety conditions. Whether that truly happened depends largely on how gain of function experiments are defined. And therein lies the problem: whether or not the lab-leak theory on the origin of Covid-19 is correct, virologists have had a long time to come to terms with gain-of-function research. Virologists must now work closely with government regulators worldwide to devise and implement reforms. Any remaining ambiguities in how gain-of-function research is defined, conducted and regulated need definitive resolutions. The risks of triggering a new human pandemic must be clearly understood and respected. We must satisfy the public that our work benefits society and does not threaten it. There are also lessons for the Chinese government. The 2003 SARS outbreak originated in a Chinese wet market when a bat-like coronavirus spread to humans. Yet China did not take all the steps necessary to reduce the risks of another coronavirus outbreak. And here we are today. If the natural-origin theory of SARS-CoV-2 is correct, animal-to-human virus transmission in China, probably associated with the wet market industry, happened again in late 2019, and this time with catastrophic consequences. The embarrassment to the Chinese government is sufficient to explain some aspects of its secrecy and/or cover-ups over the events in Wuhan in late 2019, and its later attempts to deflect the blame elsewhere. Moving forward, China must seriously deal with its wet markets and the wild animal trade, whatever the economic and cultural consequences. It has a responsibility to the rest of the world to act decisively.

The duelling lab-leak and natural-origin controversies will probably continue, not least because key political and science proponents have taken entrenched positions, their egos are involved. But however Covid-19 originated, enough knowledge has already been accumulated that can reduce the risks of further pandemics if applied by the world’s virologists and the Chinese government. Applying those insights should be the priority moving forward. And it seems to me more important that we focus on stopping SARS-CoV-2 from spreading further than from agonizing over exactly where it came from.

One further point: while it is important to understand a catastrophic event like the Covid-19 pandemic, all of us, perhaps, should be careful what we wish for. Suppose that the western world collectively concluded that the leak of a virus from the Wuhan Institute of Virology was responsible for the pandemic but was unable to provide sufficient proof to convince the Chinese government. The likely outcome would be a diplomatic and trade war that could drive a global economic depression — or worse. To justify such an outcome, the standard of proof for the origin of Covid-19 must be immaculate, and not merely based on the political rhetoric and scientific speculation that have been rife during the past two years.

A debate over whether the U.S. National Institutes of Health (NIH) funded unacceptably risky virus research in China has cast a spotlight on federal funding of what are known as gain-of-function (GOF) virology experiments. But the United States approved and funded under a 2017 policy two influenza studies that kicked off controversy over GOF research 10 years ago; they now have ended. The previously unreported development emerged quietly over the past few weeks after NIH scrubbed its website of most mentions of the words “gain of function” and the initialism “GOF,” which describe experiments that tweak pathogens to make them more infectious or transmissible. NIH says it undertook the revisions because the terms have been “misused” and are confusing. In part, the terms could lead to confusion because federal rules adopted in 2017 require only a subset of GOF studies—those involving “enhanced potential pandemic pathogens” (ePPPs)—to go through special safety and risk reviews. To meet the ePPP definition, federal officials must conclude a proposed experiment might make more dangerous a pathogen believed to have the potential to cause a pandemic.

Ten years ago, two studies judged to involve a PPP, which modified the H5N1 avian influenza virus so that it spread more easily in ferrets sparked an uproar from scientists concerned that the modified viruses could escape from the lab or fall into the wrong hands. One of the controversial studies was led by virologist Yoshihiro Kawaoka’s lab at the University of Wisconsin, Madison, the other by virologist Ron Fouchier at Erasmus Medical Centre in the Netherlands. The storm led NIH in 2014 to pause funding of those studies and other research that might constitute risky GOF (including some coronavirus studies). In 2017, after lengthy expert deliberations, the Department of Health and Human Services (HHS), NIH’s parent agency, adopted a new ‘framework’ for evaluating such experiments. It dropped the GOF terminology and adopted the ePPP moniker instead. Then, Kawaoka and Fouchier resubmitted proposals for their paused H5N1 research, which a closed-door federal panel approved and NIH funded in 2019. The review panel also approved a third project, involving the H7N9 avian influenza virus, but NIH decided to redirect the funding to “alternative approaches,” NIH’s revised site says.

Now, the two H5N1 projects have ended, the site says. The end of NIH’s only funded ePPP projects won’t defuse ongoing debate over risky pathogen research. Some critics say the ePPP definition used by the United States is too narrow and should be broadened so it would have applied to US funded experiments conducted in Wuhan in China. (Some observers claim those studies led to the coronavirus pandemic, but an NIH analysis has found the viruses studied are too genetically distant:

https://www.nih.gov/about-nih/who-we-are/nih-director/statements/statement-misinformation-about-sars-cov-2-origins

As the world has learned to its cost, the Delta variant of the pandemic coronavirus is more than twice as infectious as previous strains. Just what drives Delta’s ability to spread so rapidly hasn’t been clear, however. Now, a new lab strategy that makes it possible to quickly and safely study the effects of mutations in SARS-CoV-2 variants has delivered one answer: a little-noticed mutation in Delta that allows the virus to stuff more of its genetic code into host cells, thus boosting the chances that each infected cell will spread the virus to another cell.

That discovery, published just now, is “a big deal,” says Michael Summers, a structural biologist at the University of Maryland, Baltimore County—not just because it helps explain Delta’s ravages. The new system, developed by Nobel Prize winner Jennifer Doudna of the University of California (UC), Berkeley, and her colleagues, is a powerful tool for understanding current SARS-CoV-2 variants and exploring how future variants might affect the pandemic, he says. “The system she has developed allows you to look at any mutation and its influence on key parts of viral replication. … That can now be studied in a much easier way by a lot more scientists”:

https://www.science.org/doi/10.1126/science.abl6184

Researchers analysing how mutations in the coronavirus’ genome affect its activity have concentrated on the spike protein, which studs the virus’ surface and allows it to invade human cells. That’s partly because, short of deliberately mutating the virus and testing it—research that requires high-level biosafety facilities—the best tool for probing individual mutations has been what’s called a “pseudovirus,” a construct made from a different virus, often a lentivirus, that can express a coronavirus protein on its surface. But lentiviruses only express spike, not SARS-CoV-2’s other three structural proteins. Doudna made the new tool by tweaking lab constructs called virus-like particles (VLPs), which contain all the virus’ structural proteins but lack its genome. From the outside, a SARS-CoV-2 VLP looks exactly like the full-fledged virus. It can bind with cells in a laboratory and invade them. But because it is stripped of the virus’ RNA genome, it can’t hijack a cell’s machinery to replicate and burst out of the host cell to infect more cells. “It’s a one-way ticket. It doesn’t spread,” says Charles Rice, a molecular virologist at Rockefeller University. Doudna also added a new innovation to the VLP system. They inserted a snippet of messenger RNA (mRNA) that causes cells invaded by the VLPs to light up and glow. The brighter the cells glow after being infected with the VLPs, the more mRNA the VLPs have successfully delivered.

Next, the researchers tweaked the VLP’s proteins with various mutations. One was R203M, a mutation found in Delta that alters the nucleocapsid (N), a protein tucked inside the virus that packages its RNA genome. The N protein is a central player in viral replication, with roles that include stabilizing and releasing the virus’ genetic material. And it contains a mutational hot spot: a seven–amino acid stretch that is mutated in every SARS-CoV-2 variant of interest or concern in most samples studied. R203M is one mutation in this hot spot. That work “revealed a surprise,” Doudna says. According to the intensity of the VLP’s glow, “A single amino acid change found in Delta’s nucleocapsid protein supercharged the particles with 10 times more mRNA compared with the original virus!” Cells infected with VLPs carrying N mutations found in the Alpha and Gamma variants glowed 7.5 and 4.2 times brighter, respectively.

The scientists next tested a real coronavirus engineered to include the R203M mutation, in appropriate lab biosafety conditions. After invading lung cells in the lab, the mutated virus produced 51 times more infectious virus than an original SARS-CoV-2 strain. In people infected with the coronavirus, a very small proportion of viral particles produced by a cell actually go on to infect another cell, in part because many viral particles lack parts or all of the viral RNA genome. So mutations that make the virus more efficient at putting RNA inside host cells can boost the number of infectious particles produced. “This mutation that’s found in Delta … makes the virus better at making infectious particles and because of that, it spreads more quickly,” says Abdullah Syed, a biomedical engineer at the Gladstone Institute and one of the paper’s first authors. The researchers are now trying to understand just how Delta’s R203M mutation and others in N improve the assembly of viral particles and their mRNA delivery to host cells. They will probe whether a host protein is involved. If so, targeting it with a drug could be an effective way to stall Delta’s spread.

 

Prof. Justin Stebbing

 

Vaccination campaigns in most countries have reached phased progress

Vaccination campaigns in most countries have reached phased progress

Record cases in France, Portugal, Turkey, Italy, Sweden, the Netherlands and Israel; Italy will mandate vaccines in >50 year olds in public sector…

Read more
Omicron leads to milder disease compared to the Delta variant

Omicron leads to milder disease compared to the Delta variant

Macron said “I am not about pissing off the French people. But as for the non-vaccinated, I really want to piss them off. And we will continue…

Read more
Evidence of Omicron taking over and even breaking through lockdowns has led to cases rising ‘everywhere’

Evidence of Omicron taking over and even breaking through lockdowns has led to cases rising ‘everywhere’

The UK released vaccine efficacy data against Omicron hospitalisations this week, showing an estimated efficacy of 88% 2 weeks after a booster dose,…

Read more
Top