virology blog

About viruses and viral disease

Vincent Racaniello

A whale of a virus story

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The ancestors of cetaceans (whales, dolphins, and porpoises) moved from land to the sea over 50 million years ago. Many viruses infect cetaceans, but how they evolved during the shift from land to sea is unknown. Fossilized retroviral genomes integrated into cetacean DNA provide insight into this question.

The retroviral reproduction cycle involves the conversion of viral RNA into DNA followed by integration in host chromosomes, leading to what is know as proviral DNA. If this integration event occurs in germ cells, the provirus may be transmitted to offspring for many generations. Analysis of cetacean endogenous retroviral DNA (ERV) provides insight into when in evolution these viruses were acquired.

Cetacean retroviruses may have arisen in two ways. In the land-to-water scenario (pictured), the terrestrial ancestor of cetaceans was infected, and then carried the retrovirus into the oceans. In the secondary host switching scenario, only after cetaceans were in the oceans were they infected by cross-species transmission from other non-cetacean mammals.

Analysis of cetacean ERVs provides support for both scenarios. A search of the sequenced genomes of mysticetes (baleen whales) and odontocetes (toothed whales) revealed 8,724 ERVs. Phylogenetic analysis of these ERVs places them into 315 distinct lineages. Of these, 298 are found in both mysticetes and odontocetes, implying that they were present before these lineages diverged. The copy numbers of these ERVs are very low, suggesting that they did not proliferate after their hosts entered the waters. Some are related to ERVs found in hippopotamuses, which share a common ancestor with cetaceans, and are even found the the same location in the genomes.

Another 17 lineages were not common to mysticetes and odontocetes, but are found in specific sub-lineages of cetaceans. This observation suggests that they were acquired from other non-cetacean mammals. In support of this hypothesis, it was found that these ERVs are closely to ERVs in a variety of land mammals including bats and cows. These ERVs are more numerous in the cetacean genome, implying that they entered recently and might still be infecting these mammals. Whether or not the infections have pathogenic consequences is unknown.

The reader might be asking how a whale might acquire a virus from terrestrial and semi-aquatic mammals. Apparently there is more interaction of cetaceans with these animals than we think: killer whales have been observed feeding on terrestrial mammals and seals.

Given the difficulty in sampling cetaceans, it will be difficult to determine how other viruses originated in these animals. This question can be readily addressed for endogenous retroviruses because they are integrated into germline DNA, often for millions of years.

Evolution of a bacterial protein into a virus-like, RNA binding capsid

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Starting with a bacterial protein, directed evolution in the laboratory has been used to produce a virus-like capsid that binds and protects RNA. This finding has implications for the origins of viruses.

One view of the evolution of life is that viruses were present even before the first cells in the form of self-replicating molecules. These were technically not viruses, because they did not need cells for their replication. The idea is that when cells did arise, the replicators invaded them and then recruited host proteins for the formation of capsids.

The starting point for experiments intended to provide insight into how a protein might become a viral capsid is a bacterial protein, lumazine synthase, that forms 60-subunit particles that have no affinity for nucleic acids. The protein was redesigned and linked to a peptide that binds to an RNA stem-loop called BoxB. It was then further modified for the ability to package an mRNA that encodes the synthase. Packaging was stimulated by adding BoxB tags to the ends of the mRNA. However, only one of 8 particles packaged the mRNA.

To improve the capsid, the bacterial gene was mutagenized and capsids were selected by rounds of incubation with ribonuclease of smaller and smaller size. The idea was that this strategy would select for capsids that not only packaged the mRNA but would protect it from RNAse digestion. The result was a protein that could form a capsid called NC-4 (pictured) which encapsidated mainly the mRNA and protected it from digestion.

The changes that occurred during this evolution process led to the production of what looks very much like a viral capsid. It is composed of 240 protein subunits arranged in pentamers and hexamers with t=4 icosahedral symmetry*. The amino acid changes that led to the formation of this capsid can be readily discerned. The pores on the capsid are very small, explaining its relative nuclease resistance compared with earlier versions. In addition, the RNA appears to play a role in assembly of the capsid. Finally, changes in the mRNA appear to have led to formation of a stem-loop which facilitates packaging of the nucleic acid into the particle.

These results are amazing: we know that arranging proteins with icosahedral symmetry is an efficient way to build a stable virus particle with the least number of subunits, confirmed by the directed evolution of an icosahedrally ordered and stable capsid.

These observations have multiple implications. They show how ancient self-replicating RNA molecules, the precursors of viruses, might have recruited a host protein and driven its evolution into a protective capsid that specifically packages only the viral RNA. They also indicate how stable particles might be designed as alternatives (dare I say improvements?) to viruses for therapeutic purposes, such as gene therapy and vaccination.

*If you do not understand what icosahedral symmetry is or what t=4 means, please watch my lecture on virus structure.

The remarkable diversity of bat coronaviruses

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All human viruses, including SARS-CoV-2, arose from spillovers from other animals. Results of a recent study of bat samples collected in a small region of Yunnan Province, China revealed additional close relatives of SARS-CoV-2 and SARS-CoV.

After the identification of SARS-CoV-2 in early 2020, wildlife sampling and retrospective genome sequencing revealed highly related viruses in animals. The virus RaTG13, from Rhinolophus affinis, shares the highest overall genome identity with SARS-CoV-2, 96.10%. The virus RmYN02 from the bat R. malayanus is the closest relative of SARS-CoV-2 in the ORF1ab open reading frame. Pangolin viruses from Guangdong have identical amino acids at six key residues in the receptor binding domain (RBD) needed for binding to human ACE2. A more distantly related coronavirus was isolated from a bat in Japan, and two viruses from Cambodia have 92.6% genome identity with SARS-CoV-2 and share five of six critical amino acids in the RBD. Finally a bat coronavirus from Thailand is closely related to RmYN02. These observations demonstrate that bats from a broad part of Asia harbor close relatives of SARS-CoV-2.

Fecal samples, oral swabs, and urine samples collected from mainly horseshoe bats in a small area of Yunnan Province between May 2019 – November 2020 were analyzed by RNA sequencing. The results revealed 9 novel betacoronaviruses and 17 alphacoronaviruses. Four of the betacoronaviruses were related to SARS-CoV-2 and three were related to SARS-CoV. Rhinolophus pusillus virus RpYN06 was the closest relative of SARS-CoV-2 in most of the genome with the exception of the spike gene. The other three SARS-CoV-2 related coronaviruses encode a spike gene that could weakly bind to the hACE2 receptor in vitro. Patches of high sequence identity in different regions of the genome illustrate the work of extensive recombination events.

While all the viruses identified in this study, as well as the previously discovered RmYN01 and RmYN02, were identified in a 1100 hectare part of Yunnan province, the results of ecological modeling show that many species of rhinolophid bats are present in much of Southeast Asia and southern China. Numerous other bat species and other wildlife inhabit this area, many of which can be infected by SARS-CoV-2. Hence much more wildlife sampling is needed to track potential spillovers of viruses into humans.

These findings also demonstrate that a very large part of Asia might harbor the direct ancestor of SARS-CoV-2. Remember that HIV/AIDS was first detected in Los Angeles in 1981 but the virus spilled over from a chimpanzee to a human in Africa in ~1920.

Holiday travel explains spread of a SARS-CoV-2 variant

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The emergence and spread throughout Europe of a SARS-CoV-2 variant, 20E (EU1) in the summer of 2020 illustrates how a virus may become dominant not by increased transmissibility but through travel and lack of effective containment and screening.

The SARS-CoV-2 variant 20E (EU1) emerged in Spain in the summer of 2020 and spread to multiple European countries. By the fall of 2020 most of the sequences in Europe were from 20E (EU1). The variant bears a number of amino acid changes including A222V in the N-terminal domain of the spike protein (pictured).

Results of binding and neutralization assays revealed that the A222V change did not affect interaction of the spike protein with polyclonal or monoclonal antibodies. Lentivirus particles bearing the spike with A222V did not reproduce with higher efficiency in cells in culture. Authors conclude that these observations are not consistent with increased transmissibility of the 20E (EU1) variant. However, I would argue that studying the infectivity of a pseudotyped virus – in this case a lentivirus bearing the SARS-CoV-2 spike – in 293 cells (possibly human embryonic kidney) has virtually no relevance to what occurs in humans. At the very least, authentic SARS-CoV-2 infection of human respiratory tract cells must be examined. Even then, the results may have no direct bearing on what occurs in humans.

In contrast, epidemiological evidence explains the spread of 20E (EU1). This variant arose first in Spain in early summer 2020. It then spread extensively in Spain and also spread to other European countries. Results of modeling indicate that the spread of the variant can be explained by holiday travel-associated transmission (many EU countries opened their borders to travel on 15 June), and human behaviors such as failure to distance, mask, restrict gatherings, and adequately test for infections.

It seems likely that human behavior might also account for the global spread of other SARS-CoV-2 variants (e.g. alpha and beta). Authors believe that such spread is due to increased inherent transmission of the viruses, but the data in support of this conclusion are not convincing. Increased reproduction of pseudotyped viruses in cells in culture, as pointed out above, is likely irrelevant. Increased shedding of viral RNA from the nasopharynx, detected by PCR, is also irrelevant as it does not represent infectious virus. In no case has shedding of infectious virus from the nasopharyngeal tract been studied to address potential mechanisms of increased transmission. It is claimed that the reproductive index of variants is increased, but these calculations are flawed. The reproductive index is determined by a formula that includes both viral and host factors. However, host factors are never included when this index is determined for individual variants. As the study above indicates, human activities can substantially affect predominance of a virus in a population.

Why do variants out-compete and displace other viruses? It is because the variants have increased fitness, the ability of a virus to reproduce in the host. Fitness can be altered in many ways, including evasion of antibody responses, increased particle stability, and even person to person transmission. No experiments have been done to explain the increased fitness of variants. Fitness is not the same as transmission.

Variants of influenza virus arise frequently, and these variants displace existing viruses because they have a fitness advantage. For influenza virus, a fitness advantage is often conferred by HA amino acid changes that allow escape from antibody neutralization. Antigenic variants can infect a slightly larger number of hosts and that is enough natural selection advantage for the new variants to outcompete the older ones. No one ever says that these influenza virus variants have increased transmission.

Unfortunately the narrative that the variants have increased transmission is dominating the media. This situation has arisen because virologists, epidemiologists, and evolutionary biologists are not talking to one another. In addition, what we know about other viruses, as illustrated here for influenza virus, is also ignored.

T cells will save us from COVID-19, part two

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T cells are the other arm of the adaptive immune response (in addition to B cells) that are essential for clearing virus infections. Most studies of immunity to SARS-CoV-2 infection have focused on antibodies and their ability to neutralize virus infection. The observation that variants of concern are less effectively neutralized by antibodies against ancestral strains have led to predictions of vaccine failure and doom. This outlook is incorrect: amino acid changes in the spike protein of SARS-CoV-2 variants of concern do not impact T cell reactivity and are not likely to affect the ability of T cells to clear infection. This conclusion has been emphasized by the results of another study which show that SARS-CoV-2 variants of concern partially escape humoral but not T-cell responses in COVID-19 convalescent donors and vaccinees.

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. 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.

A study of antibody and T cell responses to SARS-CoV-2 and variants of concern B.1.1.7 and B.1.351 was carried out in a cohort of health care workers vaccinated with BNT162B2 mRNA vaccine. Some of these individuals had recovered from COVID-19 and received a single vaccine dose, while others had not been infected and received two vaccine doses.

Plaque assays were used to show that vaccine-induced antibodies neutralized the infectivity of B.1.1.7 virus as well as ancestral SARS-CoV-2. However, neutralization titers against the B.1.135 variant were about 4-fold lower.

To examine T cell responses to vaccination, blood mononuclear cells (PBMC) were stimulated with peptides from the spike protein. PBMC from immunized patients were activated equally by peptides spanning the entire spike protein from the ancestral virus, or from peptide pools covering the regions of spike that are changed in the variant viruses. As shown previously, T cell epitopes in the spike protein of variants of concern do not functionally change.

We can deduce the meaning of these findings for infection with variants of concern. In theory, should a variant fail to be efficiently neutralized by antibody in an individual previously infected with ancestral virus, or vaccinated (with ancestral spike protein), the T cells should still be able to prevent spread of infection and severe disease or death. This hypothesis is supported by the outcome of trials with the Johnson & Johnson Ad26.COV2-S vaccine, an adenovirus vectored spike vaccine. Sera from volunteers in South Africa, where B.1.351 circulates, had a tenfold reduced neutralization titer against that variant of concern. However, the vaccine was 100% effective in preventing hospitalization and death due to COVID-19 – likely a consequence of virus-specific cytotoxic T cells.

The situation with other vaccines is less clear. The AZD1222 vaccine, which showed 70% efficacy in the UK, showed only 22% efficacy in South Africa against mild to moderate COVID-19. Whether or not this vaccine would prevent severe COVID-19 could not be assessed as there was no serious disease observed during this trial.

The B.1.1.7 variant has the N501Y change in the spike protein, while B.1.351 and P.1 (Brazil) have in addition the amino acid changes K417N/T and E484K. Variant B.1.617 (India) has E484Q and L452R; the latter is also present in CAL variants. Given that none of these changes alter T cell reactivity it is likely that spike vaccines will protect against serious disease and death caused by these variants. Reports of reinfection with such variants in previously vaccinated individuals that leads to serious disease should be taken with a large grain of salt.

Novel human coronaviruses from pigs and dogs

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The seven human coronaviruses have all originated from spillover events from a variety of nonhuman animals, including bats, rodents, and camels. Recently isolated coronaviruses from humans appear to have originated in pigs and dogs.

Three of 369 plasma samples collected between May 2014 and December 2015 in two schools in Haiti were found to be positive for coronavirus. All three children had fever, and one reported cough and abdominal pain. Whole genome sequence analysis of all three isolates revealed them to be porcine deltacoronaviruses (PDCoV). The human coronaviruses known to date are alpha- and betacoronaviruses.

PDCoV was first identified in 2012 in Hong Kong and then in 2014 in the Americas. The virus infects epithelial cells in the jejunum and ileum and the large intestine, leading to gastrointestinal symptoms. No PDCoV infections have been reported in Haitian domestic pigs.

The PDCoVs isolated four months apart from two children attending the same school are closely related to a virus isolated from pigs a year later in China. The other Haitian child was infected with PDCoV that is more closely related to an isolate from pigs in Arkansas from 2015. The implication of sequence analysis is that two separate zoonotic transmissions took place. How the viruses traveled from the US and China to Haiti is not clear.

All three PDCoV human isolates share a signature of amino acid changes in the viral ORF1a/b and spike proteins that is not seen in other PDCoV isolates. These changes might have been selected during reproduction in human hosts.

In a separate study, 8 of 301 nasopharyngeal swabs from patients hospitalized between 2017-2018 with pneumonia in Malaysia were shown to harbor canine coronavirus (CCoV), an alpha coronavirus. Close analysis of the genome sequence revealed that the virus is a recombinant, with most of the genome originating from CCoV and part of the spike from feline coronavirus.

Canine and feline coronaviruses cause moderate to severe intestinal disease in dogs and cats. The viruses have a worldwide distribution and given the prevalence of these animals as pets, it is not surprising that human infections may occur, albeit rarely. The eight patients who harbored this novel CoV were children living in areas where exposure to domestic animal and jungle wildlife would be expected, possibly explaining how the infections were acquired.

These human infections with porcine and canine coronaviruses appear to be isolated incidents which did not lead to extensive human transmission. Nevertheless the findings emphasize the public health threat of animal coronaviruses and the need for improving our surveillance for these viruses.

A genetically stable attenuated poliovirus vaccine

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Eradication of poliomyelitis appears to be on track: types 2 and 3 polioviruses have been declared eradicated, and in the past 12 months there have been just 338 cases of type 1 polio in Afghanistan and Pakistan. But there have also been 491 cases of polio caused by the type 2 Sabin vaccine. The development of a modified version of the type 2 vaccine component could improve this situation.

The oral poliovirus vaccines (OPV) developed by Albert Sabin have played a huge role in reducing cases of polio globally from 400,000 a year in 1980 to the current numbers. Their success, however, comes with a cost: they may in rare cases cause the disease they are designed to prevent. The three serotypes of OPV are taken orally and then reproduce in the intestines where they confer effective immunity to polio. During reproduction of the viruses in the intestine, the mutations originally selected by Sabin to eliminate the neurovirulence of the viruses are lost. Most immunized children shed vaccine revertants, and about 1 in 1.4 million vaccine recipients contract polio.

These vaccine revertants also circulate extensively throughout the human population, and may cause outbreaks of polio in areas where vaccine coverage drops. To address this problem, in 2016 WHO removed the type 2 component of poliovirus from OPV, which is responsible for most of the vaccine-associated cases. However vaccine-derived type 2 polioviruses continue to circulate even after this vaccine withdrawal and have caused a number of outbreaks. The response to control these outbreaks is to conduct mass immunizations with OPV type 2 – which re-introduces vaccine-derived polioviruses into the environment.

The solution might be to develop a more genetically stable strain of type 2 OPV. Such strains have been developed by leveraging advances in basic research on polioviruses that have been carried out since the 1980s. A new OPV2 strain (nOPV2) was developed by introducing three different types of changes in the OPV2 genome. First, mutations were introduced in the 5’-noncoding region of the viral RNA in the area of a single base that is a major attenuating mutation in OPV. These changes were designed to stabilize this region against reversion. Second, an RNA stem loop structure called the cre element, which is essential for viral RNA synthesis, was relocated from its original position in the genome to the 5’-noncoding region. This alteration should prevent RNA recombination that would replace the viral 5’-end with that of other enteroviruses, thereby removing the stabilizing changes. Finally, the RNA polymerase was modified so that it made fewer copying errors and had reduced recombination frequency.

The resulting nOPV2 was tested extensively in cells in culture and in experimental animals to demonstrate that the virus did not revert within the 5’-noncoding region, did not recombine with other enteroviruses, and maintained an attenuation phenotype in animals.

Based on these findings nOPV2 and another redesigned strain produced by codon-deoptimization were tested in a phase I trial. The adult volunteers, previously immunized with poliovirus vaccine, were housed in a containment facility to prevent environmental release of nOPV2. After oral administration of either vaccine, adults were monitored for symptoms, induction of immunity, and reversion of the virus to neurovirulence. The results indicated that the nOPV2s are safe, immunogenic, and do not revert to neurovirulence, while maintaining a stable 5’-noncoding region.

Pending ongoing phase 2 trials, nOPV2 is likely to be licensed for use in quelling outbreaks of type 2 vaccine-derived polio. It cannot be tested for efficacy because there are insufficient cases of polio anywhere to allow such a study. It is hoped that the excreted vaccines will not revert to neurovirulence and will circulate for a limited time in humans, as suggested by the preclinical data, thereby eliminating type 2 vaccine-induced polio. However, the numbers of subjects in the clinical trial have been small, and the selection pressure imposed by thousands of human guts might change this outcome. Viruses have been known before to defy our expectations.

Defective genomes modulate respiratory syncytial virus pathogenesis

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During viral replication, defective genomes may arise that lack essential sequences. These so-called defective genomes cannot replicate unless they are in the same cell as a helper virus. Defective genomes play a role in modulating pathogenesis of respiratory syncytial virus in humans.

Copy-back defective viral genomes (cbDVGs) of RSV arise when the viral RNA polymerase halts and then turns around and begins copying the nascent strand (illustrated below – image credit). Because the cbDVGs have strands of both (+) and (-) polarity it is possible to design primers to amplify them by RT-PCR.

It has been suspected that defective viral genomes might modulate viral pathogenesis because they are efficient inducers of interferon. In a study of 122 hospitalized pediatric patients with RSV infection, the presence of cbDVGs was associated with higher viral loads and longer hospitalizations. Furthermore, patients harboring cbDVGs had higher expression of pro-inflammatory cytokine genes.

Unexpectedly, non-hospitalized patients with confirmed RSV infection also had high levels of cbDVGs and high viral loads. Analysis of the kinetics of cbDVG production revealed that when cbDVGs arise early in infection, less severe symptoms present. In contrast, when cbDVGs arise later in infection, higher viral loads and more severe disease occur. The latter patients also produce higher levels of pro-inflammatory cytokines which likely cause immunopathogenesis.

An interpretation of these findings is that when cbDVGs arise early in infection, they induce antiviral immune responses that limit viral replication and disease. When cbDVGs arise later, the virus has already reproduced to high levels, leading to more severe disease. The factors that regulate cbDVGs production are not known, but could involve sex, age, immune status, and the levels of the defective genomes in the virus inoculum.

These results are of interest because it has not been possible to predict which RSV infected patients will develop severe disease. It might be possible to use levels of cbDVGs to forecast clinical outcome.

When defective viral particles were discovered many years ago, Alice Huang proposed that they might modulate viral pathogenesis. It was not until the 1990s that the technology became available to test this hypothesis. The results with RSV suggest that whether cbDVGs are beneficial or detrimental depends on when they arise in infection.

SARS-CoV-2 variants arise during individual infections

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Early in the COVID-19 pandemic, SARS-CoV-2 genome variation appeared to be low, with an average of 10 base differences in the 30,000 base genome between any two isolates. Late in 2020, as many more people were infected, variants were isolated that had more changes than previously seen. A study of variation at the genome level indicates that diversity in a single host has been underestimated.

SARS-CoV-2 variants certainly arise in each infected individual, and these may be subjected to selection pressures such as those imposed by antibodies binding to spike protein. Commonly used sequencing technologies do not permit detection of virus variants within single samples. To address this limitation, a high-throughput sequencing method was developed for sequencing individual virus RNA genomes in patient samples. The results demonstrate that SARS-CoV-2 variants emerge in each host and are subject to immune selection pressure.

When this method was used to analyze a patient isolate of SARS-CoV-2 after four passages in Vero cells, in the regions encoding spike, ORF3, envelope, and M protein, 18 unique combinations of mutations were detected. Over half of the single genome sequences differed from the reference sequence. Many of the changes led to amino acid substitutions, suggesting selection pressure occurring during cell culture adaptation.

In-host diversity was then examined for 7 patients sampled between days 8 and 17 of illness onset. Only a few sequence haplotypes were detected, with no clear consensus among the amino acid changes. These relatively homogeneous sequences might have been a consequence of sampling early in infection when limited antibody pressure was present. Examination of the antibody response in longitudinal samples revealed an increasing and broadening antibody response to the spike.

A study of antibody responses and presence of mutations in individual genomes revealed a correlation between the emergence of antibodies to the N-terminal domain of spike protein, the emergence of amino acid changes in regions that bind these antibodies, and a delay in clearance of virus. These results are consistent with antibody pressure during infection leading to selection of SARS-CoV-2 spike variants (pictured).

SARS-CoV-2 variation in a single host had not been previously described, probably due to the inability of previous sequencing methods to distinguish variation from technical errors. It is also likely that high-quality data were acquired early in infection when viral titers are high yet antibody pressure is not yet present.

There are several take-home messages from these findings. They illustrate how diversity in a single host might give rise to antibody-resistant variants that could spread in a population if they have the appropriate fitness. In-host escape might be avoided by containing viral reproduction early in infection, either by prior immunity or by antiviral therapy, before selection by antibody takes place. This method should be applied to studying more COVID-19 patient samples to understand the extent of potential in-host SARS-CoV-2 variation.

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

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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.