virology blog

About viruses and viral disease

Commentary

SARS-CoV-2 variant B.1.1.7 is not more virulent

by

coronavirus

When the B.1.1.7 variant of SARS-CoV-2 was first detected in the UK in December 2020 it was accompanied by unsubstantiated claims of increased transmissibility and virulence. The results of a hospital-based study in London reveals no association of the variant with severe disease in this cohort.

In a note published by NERVTAG on 21 January 2021, the panel concluded that ‘there is a realistic possibility that infection with VOC B.1.1.7 is associated with an increased risk of death compared to infection with non-VOC viruses.’ The death risk ratio for VOC infected individuals compared with non-VOC infected individuals was 1.65. This conclusion was based on analysis of COVID-19 related deaths at several hospitals in the UK. The authors noted in this report that ‘The data set used in the LSHTM, Imperial, Exeter and PHE analyses is based on a limited subset of the total deaths. This includes approximately 8% of the total deaths occurring during the study period’.

In the present study, SARS-CoV-2 PCR-positive samples from hospitalized patients were analyzed that had been collected between 9 November and 20 December 2020 in London. Of these, 341 (58%) were infected with B.1.1.7 and 143 (42%) were infected with an ancestral virus. Results of statistical models showed no association between severe disease and death and the B.1.1.7 lineage.

I hope that these results can begin to reverse the disturbing narrative advanced by some that B.1.1.7 is 50% more virulent than its ancestor. This conclusion was never firmly grounded, yet it has been echoed by mainstream media as if it were dogma.

Unfortunately the authors of this paper continue to promote the idea that B.1.1.7 viruses are more transmissible. Their conclusion is based on increased levels of viral RNA in patient samples as determined by RT-PCR (cycle threshold 28.8 in VOC infected patients versus 32.0 in non-VOC infected patients) and genomic reads by sequencing (1280 vs 831). Increased viral load determined by these methods might be an indication of increased viral fitness, but it does not prove increased transmission. It is not known if VOC-infected patients shed more infectious virus, which might be consistent with increased transmission. Until such experiments are done, it can only be speculated that B.1.1.7 and other VOC have increased transmissibility.

T cells will save us from COVID-19

by

In our quest to stop the COVID-19 pandemic by vaccination, we have been myopically focussed on inducing antibodies against the spike protein. As variants of SARS-CoV-2 have emerged that reduce the ability of such antibodies to block infection, concern has arisen that we will not be able to halt the disease. Such concerns appear to ignore the other important arm of the adaptive immune response: T cells.

Anti-viral antibodies can prevent infection of cells, but when antibody titers are low – years after infection or vaccination – some cells will inevitably be infected. In this case, T cells come to the rescue. Cytotoxic T cells can sense that a cell is infected and kill it (illustrated). T cells sense infected cells by virtue of viral peptides that are presented by major histocompatibility molecules on the plasma membrane. Such T cell peptides may be produced from nearly any viral protein. In contrast, only certain viral proteins, like the spike of SARS-CoV-2, can give rise to antibodies that block infection.

The T cell response to SARS-CoV-2 infection has been largely ignored for the past year. Certainly, some laboratories have studied T cell responses in patients, and the vaccine makers have dutifully included them along with assays for neutralizing antibodies. But the dialogue has never included T cells as important for resolving disease – but they are for most viral infections. Because T cells can kill virus infected cells, they can help prevent disease and end the infection.

The recent finding that amino acid changes in the spike protein of SARS-CoV-2 variants of concern do not impact T cell reactivity is very good news. In this study, the authors synthesized short peptides covering the entire proteome of multiple SARS-CoV-2 isolates, including the original Wuhan strain, and variants B.1.1.7, B.1.351, P.1, and CAL.20C. They found little difference in the ability of T cells from either convalescent or vaccinated patients to recognize peptides from these viruses. This result means that the amino acid changes in the variants are not likely to impact the ability of T cells to clear infection.

This observation explains why some COVID-19 vaccines have effectively prevented hospitalization and death even in regions where variants circulate widely. In some cases the ability of sera from vaccinated individuals have reduced ability to neutralize infection with some variants. Nevertheless, the vaccines prevent severe COVID-19 and death because T cells can still recognize variant virus-infected cells and clear them.

It’s highly unlikely that vaccination will prevent infection with SARS-CoV-2. Antibody levels rapidly decline after infection or vaccination, especially in the respiratory mucosa. When a virus enters the nasopharynx of an immune individual, it will encounter little antibody opposition and will initiate an infection. However memory B and T cells will spring into action and within a few days produce virus-specific antibodies and T cells. The antibodies will limit infection while the T cells will clear the virus-infected cells. The result is a mild or asymptomatic infection that likely is not transmitted to others.

The recent observations that vaccination appears to prevent asymptomatic infections is a red herring. These studies are being done soon after vaccination when antibody levels in serum and mucosa are high. If these studies were done a year after immunization, the results would be quite different.

Now imagine that you are fully vaccinated and become infected with a SARS-CoV-2 variant. The virus may begin to reproduce rather well in the nasopharynx even in the face of a memory response, because the antibodies are just not good enough to block infection. T cells to the rescue: the T cell epitopes on the surface of the infected cells are readily recognized because they are mainly the same in the variants as in the ancestral strain of SARS-CoV-2. You may have a mild infection but you will not be hospitalized or die. Isn’t that the goal of vaccination?

Why don’t T cell epitopes change as do B cell (antibody) epitopes? A B cell epitope is the same in everyone and so if a virus emerges with a slightly different epitope, it will evade antibody in anyone infected with that virus. T cell epitopes are different. T cell epitopes are presented to T cells on the infected cell surface by MHC molecules, which are encoded by highly polymorphic genes. That means that your MHC is likely different from mine, and so will be the viral peptides displayed in them. So if a T cell epitope varies during your infection, it won’t matter to other people – their infected cells will be displaying different T cell peptides.

It is possible that SARS-CoV-2 will continue to produce altered spike proteins that will completely evade antibody neutralization. In this case T cells might not be enough to prevent severe disease – they could be overwhelmed by so many infected cells. Our rush to make vaccines – understandable given the urgency – have led us to such a situation. Most of the vaccines were based only on the spike protein. If we change the spike protein to accommodate variants, we might get in a never-ending cycle of changing COVID-19 vaccines on a regular basis. A better approach would be to produce second-generation COVID vaccines that include other viral proteins besides spike protein. Inactivated and attenuated vaccines fall into this category; another solution would be to modify authorized mRNA vaccines to encode additional viral proteins.

SARS-CoV-2 variants of concern

by

In recent months variants of SARS-CoV-2 have been detected that are unusual in that they have many more genome mutations than previously found. These have been called ‘variants of concern’ (VOC) as it has been suggested that the genome mutations might impact transmission, immune control, and virulence. Below I cover each of these issues separately.

Transmission

The SARS-CoV-2 lineage called B.1.1.7 arose in the United Kingdom in September 2020 and harbors 17 genomic mutations, some of which lead to amino acid changes in the spike protein (pictured). Similar but distinct variants have been detected in other locations, including South Africa (B.1.135) and Brazil, but the B.1.1.7 lineage has been best studied. A good summary of the changes can be found in this manuscript. A number of lines of evidence have led to the conclusion that viruses of the B.1.1.7 lineage may have increased transmissibility compared with previous isolates. These include the rapid displacement of previous variants in the UK within a short period of time; an apparent increase in the R index for such variants; and increased levels of viral RNA in nasopharyngeal washes as measured by PCR or RNA sequencing.

The virological definition of transmission is the movement of viruses from one host to another. In the case of SARS-CoV-2, such transmission occurs when infectious virus particles are exhaled within respiratory droplets and arrive in another host, where they initiate infection. The evidence cited above for increased transmission of the B.1.1.7 lineage are all indirect and do not prove that the variants actually transmit, in a virological sense, better between hosts. The population growth of the variant could, for example, be a consequence of changes in human behavior. The R index, a measure of transmisssibility, is influenced not only by the virus but by human behavior. The finding of increased levels of RNA in nasopharyngeal wash is also inconclusive with respect to transmission. Viral RNA is not the same as infectious virus, and no studies have been done measuring shedding of infectious virus from individuals infected with variants of the B.1.1.7 lineage compared with other variants.

There is no doubt that the B.1.1.7 lineage has rapidly displaced others in the UK. Whether this behavior is due to an increased ability of the virus to be transmitted form one host to another has not been demonstrated. The variant has also been detected in other countries and its dispersion in those locations are not consistent with increased transmission (as I have defined above). For example, we now know that the B.1.1.7 lineage was present in the US 5-6 weeks before its detection in the UK, yet as of January it comprised just 0.3% of cases nationally. After 2 months of circulation in California, the lineage is estimated to account for 0.4% of cases compared with 1.2% at a similar point in the UK. In Florida the lineage is associated with higher spread, 0.7% of cases, but this is not the situation in other US states.

These data emphasize that we cannot conclude that the B.1.1.7 lineage is biologically more transmissible. Multiple factors are likely at play, and this is why it is better to view the B.1.1.7 lineage variants and others in terms of their fitness – the reproductive success of the virus. Many factors can influence fitness, not just transmission. These could include increased physical stability of the particle, increased resistance to immune responses, longer duration of virus presence in the nasopharynx, increased infectious virus produced within the host, more efficient establishment of infection in a host, and more. A slight increase in any of these might drive a particular variant within a population but not actually affect person to person transmission. Whether such mutations are spread by founder effect – being in the right place at the right time – also must be taken into consideration.

The statistical models that have been used to approximate the transmission of SARS-CoV-2 variants cannot prove a biological property because drive through a population can be a consequence of various fitness parameters. Experiments either in animal models (in which case the relevance to humans is unknown) or measurement of infectious virus in humans is needed. So far none of the latter have been done for the current variants.

Immune control

A more immediate concern is whether any of the changes in spike protein within VOC impact the ability of immune response to control infections. This question has been directly addressed for neutralizing antibodies, e.g. those which can block infection. Antibodies recognize specific protein sequences on the virus particle, and specifically the spike protein for those given the mRNA vaccine. Some of the spike changes identified in variants are in regions known to bind antibodies. Consequently an important question is whether vaccination can inhibit infection with the variant viruses.

This question has been addressed for both the Moderna and the Pfizer mRNA vaccines. Sera from persons immunized with mRNA-1273 efficiently neutralized pseudotyped viruses bearing the SARS-CoV-2 spike glycoprotein from the B.1.1.7 lineage. These sera had a reduced (6.4 fold) neutralization titer when the South African B.1.351 lineage was used. However these sera still fully neutralized B.1.351 with a titer of 1:290 which may be sufficient to prevent severe COVID-19. Nevertheless, Moderna has announced that it will advance a modified vaccine (mRNA-1273.351) encoding the B.1.351 amino acid changes.

In a separate study, sera from individuals vaccinated with the Pfizer BNT162b2 mRNA vaccine was tested in neutralization assays using SARS-CoV-2 viruses with selected spike amino acid changes from the B.1.1.7 (deletion of amino acids 69/70, N501Y, D614G) or B.1.351 (E484K + N501Y + D614G) lineages. These changes had small effects on neutralization with the sera. However, the engineered viruses do not contain the full set of changes found in the B.1.1.7 and B.1.351 viruses, which might explain the different results compared sera with antibodies induced by mRNA-1273.

These observations provide confidence that the two mRNA vaccines will provide protection against COVID-19 caused by currently circulating variants. However genomic surveillance must be increased to ensure that any new spike changes that might arise are detected quickly and their effects on neutralization determined.

Disease severity

A previous study did not show evidence that viruses of the B.1.1.7 lineage were associated with an increased risk of hospitalization or death. However upon examination of additional data from three separate studies NERVTAG concludes that there is a ‘realistic possibility that infection with VOC B.1.1.7 is associated with an increased risk of death compared to infection with non-VOC viruses’. This conclusion was reached by statistical analyses of reported death rates among individuals infected with VOC B.1.1.7 or non-VOC viruses. For example, in one study the relative hazard of death was 1.35 (with a 95% confidence interval of 1.08-1.68). In another study the mean ratio of case fatality ratios between cases caused by VOC or non-VOC viruses was 1.36 (95% CI 1.18-1.56). These are small differences with large confidence intervals ranging from no effect to more effect, and the authors note that the absolute risk of death remains low. The statistics are computed by analyzing a limited dataset of all COVID-19 related deaths (8%) and consequently might be in error. Furthermore, there does not appear to be an increased risk of hospitalization associated with infection by VOC viruses. My reading of this report is that it mainly serves as a warning to continue genomic surveillance of variants with respect to death risk and does not come to a conclusion on causality.

Update: Novavax just released the first results of their phase 3, spike-protein based COVID-19 vaccine. Efficacy was nearly 90% in the UK, but in a smaller trial in South Africa it was 50% against the B.1.135 variant.

Biden’s pandemic plans

by

The Biden-Harris administration has released a document describing its plans to bring the United States out of the ‘worst public health crisis in a century’. It is a roadmap for not only ending the pandemic in the US, but to re-establish leadership in the global health care community and provide assistance to other countries. I highly recommend that everyone read it (link to pdf).

The National Strategy is organized around six goals, and they are all very ambitious in their scope. They will require a massive infusion of expertise and an expansion of the public health and scientific workforce. For example, the President will establish a US Public Health Jobs Corps to increase the public health workforce and bolster clinical care capacity for COVID-19. It is a stunning collection of multi-pronged plans which rival efforts to bring the US out of the Great Depression. As President Biden has said, the federal government alone cannot execute this plan: it will require the help of many Americans.

One part of the strategy that I would like to focus on is part of goal 3, which is to “mitigate spread through expanding masking , testing , treatment , data, workforce, and clear public health standards” and in particular, the section entitled “Prioritize therapeutics and establish a comprehensive, integrated COVID-19 treatment discovery and development program”. An excerpt is below:

This includes promoting the immediate and rapid development of therapeutics that respond to COVID-19 by developing new antivirals directed against the coronavirus family, accelerating research and support for clinical trials for therapeutics in response to COVID-19 with a focus on those that can be readily scaled and administered, and developing broad- spectrum antivirals to prevent future viral pandemics.

As I have written before, the COVID-19 pandemic could have been prevented by using broadly-acting anti-coronavirus antiviral drugs. I am very happy that the Biden Administration has received this information and plans to act on it. How this goal will be achieved remains to be seen. Presumably much of this research will be done through NIH funding, but that will require an increase in the budget of that agency. Will such an increase – at least 10 billion dollars a year – be approved by Congress? Such drug discovery will also require collaboration with industry. But industry does not develop drugs for which there is currently no market. How this problem will be overcome remains to be determined.

Successful execution of this strategy will require a strong focus on science and public health, and an expansion of the workforce in these areas. I have the feeling, after reading the Strategic Plan, that the Biden-Harris administration realizes that science is the way out of this pandemic, and that science will help us with future pandemics. This attitude is welcome after four years of anti-science anti-think. How well it will be realized is unsure, given the divided nature of both Congress and this Nation. As a scientist, it is some of the best news that I have seen in years.

Musings of an anonymous, pissed off virologist

by

coronavirus

by Paul Bieniasz

Dr. Bieniasz is Professor and Investigator of the Howard Hughes Medical Institute at Rockefeller University.

As viruses go, SARS-CoV-2, is quite easy to neutralize with antibodies and, it turns out, straightforward to generate effective vaccines based on the spike protein. Perhaps, even probably, those two properties are causally related. Moreover, it appears that it is quite hard (albeit not impossible) to generate resistant spike variants that evade the polyclonal antibody responses elicited by said vaccines. This is all excellent news.

However, if I had a nefarious nature and wanted to ensure that the new SARS-CoV-2 vaccines were rendered impotent, these are a few things I would try.

First, we’d want to maximize the viral population size and diversity. Because SARS-CoV-2 has a proofreading polymerase, we might have to work hard to do this. The four measures outlined below might help accomplish this, assisting the virus to explore as much genetic diversity as possible, generating every conceivable point mutation as frequently as possible.

  • Delay the rollout of testing, so that the virus could spread undetected, seeding outbreaks in geographically, demographically and culturally diverse host populations, rendering it virtually impossible to quash with test-trace-isolate approaches.
  • Implement partial and patchy restrictions on movement and social interactions, thus maintaining consistently large pools of infected individuals.
  • Keep schools open, claiming that children don’t frequently transmit SARS-CoV-2. Because children have generally mild and perhaps more frequently asymptomatic infections, diversifying viral populations are more likely to spread undetected.
  • Start a rumor-mill, making full use of social media and other outlets, with topics such as masks are unnecessary or don’t work, that PCR tests are too sensitive or unreliable, that infection-induced ‘herd immunity’ is a reasonable strategy, or even that SARS-CoV-2 isn’t real. Undermining already inadequate public health measures helps keep viral population sizes large.

Second, during or after the establishment of large and diverse viral populations, we’d begin to apply selection pressure to enrich antibody resistance mutations. For that, we would elicit the help of the medical establishment to implement measures 5 and 6. They, laudably, want to help as many people as possible as quickly as possible — we could exploit this.

  • Treat tens of thousands of people with uncharacterized convalescent plasma of weak/unknown potency, without proper clinical trials, to get the ball rolling in applying some selection pressure to enrich for antibody resistant variants. (Again, I don’t know how effective this would be since it is mostly done in hospitals, where onward transmission would presumably be rare, but it would certainly be worth a try) Immunocompromised individuals with persistent infection might be especially helpful here.
  • Finally, and here’s the kicker: having developed a remarkable two-dose vaccine, that is extraordinarily effective, ADMINISTER IT TO MILLIONS OF PEOPLE – BUT DELAY THE SECOND DOSE. Generating a pool of hosts with just the right amount of neutralizing antibody to apply selection pressure, but also maintain sufficient levels of partially antibody-resistant virus to allow onward transmission is key here. We might not achieve this shortly after the first dose, but if we let immunity wane for a little while, say 4 to 12 weeks, we just might hit the sweet spot.

Of course, I don’t know if the above would be successful, but that’s what I’d try if I wanted to generate vaccine-resistant SARS-CoV-2 variants.

TWiV 675: Forget what you’ve herd about immunity

by

Daniel Griffin provides a clinical report on COVID-19, then we discuss Bill Foege’s letter to CDC director Robert Redfield, the false promise of herd immunity for COVID-19, secret blueprints for SARS-CoV-2 vaccine trials released, and neuropilin-1 as a possible entry protein for the virus.

Click arrow to play
Download TWiV 675 (105 MB .mp3, 174 min)
Subscribe (free): iTunes, Google Podcasts, RSS, email

Become a patron of TWiV!

Show notes at microbe.tv/twiv