Virus World

The ongoing evolution of SARS-CoV-2 continues to challenge the global immune barrier established by infections and vaccine boosters. Recently, the emergence and dominance of the JN.1 lineage over XBB variants have prompted a reevaluation of current vaccine strategies. Despite the demonstrated effectiveness of XBB-based vaccines against JN.1, concerns persist regarding the durability of neutralizing antibody (NAb) responses against evolving JN.1 subvariants. In this study, we compared the humoral immunogenicity of XBB and JN.1 lineage infections in human subjects with diverse immune histories to understand the antigenic and immunogenic distinctions between these variants. Similar to observations in naive mice, priming with XBB and JN.1 in humans without prior SARS-CoV-2 exposure results in distinct NAb responses, exhibiting minimal cross-reactivity.

Importantly, breakthrough infections (BTI) with the JN.1 lineage induce 5.9-fold higher neutralization titers against JN.1 compared to those induced by XBB BTI. We also observed notable immune evasion of recently emerged JN.1 sublineages, including JN.1+R346T+F456L, with KP.3 showing the most pronounced decrease in neutralization titers by both XBB and JN.1 BTI sera. These results underscore the challenge posed by the continuously evolving SARS-CoV-2 JN.1 and support the consideration of switching the focus of future SARS-CoV-2 vaccine updates to the JN.1 lineage.

Preprint in bioRxiv (April 22, 2024):

https://doi.org/10.1101/2024.04.19.590276 

EG.5.1 is a subvariant of the SARS-CoV-2 Omicron XBB variant that is rapidly increasing in prevalence worldwide. EG.5.1 has additional substitutions in its spike protein (namely, Q52H and F456L) compared with XBB.1.5. However, the pathogenicity, transmissibility, and immune evasion properties of clinical isolates of EG.5.1 are largely unknown. In this study, we used wild-type Syrian hamsters to investigate the replicative ability, pathogenicity, and transmissibility of a clinical EG.5.1 isolate. Our data show that there are no obvious differences in growth ability and pathogenicity between EG.5.1 and XBB.1.5, and both EG.5.1 and XBB.1.5 are attenuated compared to a Delta variant isolate. We also found that EG.5.1 is transmitted more efficiently between hamsters compared with XBB.1.5.

In addition, unlike XBB.1.5, we detected EG.5.1 virus in the lungs of four of six exposed hamsters, suggesting that the virus tropism of EG.5.1 is different from that of XBB.1.5 after airborne transmission. Finally, we assessed the neutralizing ability of plasma from convalescent individuals and found that the neutralizing activity against EG.5.1 was slightly, but significantly, lower than that against XBB.1.5 or XBB.1.9.2. This suggests that EG.5.1 effectively evades humoral immunity and that the amino acid differences in the S protein of EG.5.1 compared with that of XBB.1.5 or XBB.1.9.2 (i.e., Q52H, R158G, and F456L) alter the antigenicity of EG.5.1. Our data suggest that the increased transmissibility and altered antigenicity of EG.5.1 may be driving its increasing prevalence over XBB.1.5 in the human population.

Available as preprint in bioRxiv (Sept 1 2023):

https://doi.org/10.1101/2023.08.31.555819 

As of July 2023, EG.5.1 (a.k.a. XBB.1.9.2.5.1), a XBB subvariant bearing the S:Q52H and S:F456L substitutions, alongside the S:F486P substitution (Figure S1A), has rapidly spread in some countries. On July 19, 2023, the WHO classified EG.5 as a variant under monitoring. First, we showed that EG.5.1 exhibits a higher effective reproduction number compared with XBB.1.5, XBB.1.16, and its parental lineage (XBB.1.9.2), suggesting that EG.5.1 will spread globally and outcompete these XBB subvariants in the near future. We then addressed whether EG.5.1 evades from the antiviral effect of the humoral immunity induced by breakthrough infection (BTI) of XBB subvariants and performed a neutralization assay using XBB BTI sera. However, the 50% neutralization titer (NT50) of XBB BTI sera against EG.5.1 was comparable to those against XBB.1.5/1.9.2 and XBB.1.16. Moreover, the sensitivity of EG.5.1 to convalescent sera of XBB.1- and XBB.1.5-infected hamsters was similar to those of XBB.1.5/1.9 and XBB.1.16.

These results suggest that the increased Re of EG.5.1 is attributed to neither increased infectivity nor immune evasion from XBB BTI, and the emergence and spread of EG.5 is driven by the other pressures. We previously demonstrated that Omicron BTI cannot efficiently induce antiviral humoral immunity against the variant infected. In fact, the NT50s of the BTI sera of Omicron BA.1, BA.2, and BA.5 against the variant infected were 3.0-, 2.2-, and 3.4-fold lower than that against the ancestral B.1.1 variant, respectively. However, strikingly, we found that the NT50 of the BTI sera of XBB1.5/1.9 and XBB.1.16 against the variant infected were 8.7- and 8.3-fold lower than that against the B.1.1 variant. These results suggest that XBB BTI cannot efficiently induce antiviral humoral immunity against XBB subvariants.

Preprint (August 8, 2023) bioRxiv:

https://doi.org/10.1101/2023.08.08.552415 

Top SARS-CoV-2 variants with increased resistance to vaccine and therapeutic antibodies. Seven new lineages including BA.2.75, BA.2.75.2, BA.4.6, BF.7, BQ.1, BQ.1.1 and XBB.1 are circulating globally, with different sub-variants growing faster in different regions. Global and US frequencies of the eight  variants as of October 29, 2022 are shown. In the US, the combined pool of new variants already represents 50% of the viral genomes sequenced last week. Top graph shows the spike mutations for each lineages appearing in at least 50% of the viral genomes sequenced for each variant. Key mutations in spike conferring escape from antibodies (vaccine or therapeutics) include R346T, K444T, L452R, N460K, and F486S/V. Data from GISAID, US CDC, cov-spectrum.org, and outbreak.info used to generate the charts at https://lnkd.in/g7YYq4y

In this study, by characterizing several human monoclonal antibodies (mAbs) isolated from single B cells of the COVID-19–recovered individuals in India who experienced ancestral Wuhan strain (WA.1) of SARS-CoV-2 during early stages of the pandemic, we found a receptor binding domain (RBD)–specific mAb 002-S21F2 that has rare gene usage and potently neutralized live viral isolates of SARS-CoV-2 variants including Alpha, Beta, Gamma, Delta, and Omicron sublineages (BA.1, BA.2, BA.2.12.1, BA.4, and BA.5) with IC50 ranging from 0.02 to 0.13 μg/ml. Structural studies of 002-S21F2 in complex with spike trimers of Omicron and WA.1 showed that it targets a conformationally conserved epitope on the outer face of RBD (class 3 surface) outside the ACE2-binding motif, thereby providing a mechanistic insights for its broad neutralization activity. The discovery of 002-S21F2 and the broadly neutralizing epitope it targets have timely implications for developing a broad range of therapeutic and vaccine interventions against SARS-CoV-2 variants including Omicron sublineages.

Published in Science Advances (October 5, 2022):

https://doi.org/10.1126/sciadv.add2032 

On August 30, 2021, the WHO classified the SARS-CoV-2 Mu variant (B.1.621 lineage) as a new variant of interest. The WHO defines "comparative assessment of virus characteristics and public health risks" as primary action in response to the emergence of new SARS-CoV-2 variants (https://www.who.int/en/activities/tracking-SARS-CoV-2-variants/). Here, we demonstrate that the Mu variant is highly resistant to sera from COVID-19 convalescent and BNT162b2-vaccinated individuals. Direct comparison of different SARS-CoV-2 spike proteins revealed that Mu spike is more resistant to serum-mediated neutralization than all other currently recognized variants of interest (VOI) and concern (VOC). This includes the Beta variant (B.1.351) that has been suggested to represent the most resistant variant to convalescent and vaccinated sera to date (e.g., Collier et al, Nature, 2021; Wang et al, Nature, 2021). Since breakthrough infection by newly emerging variants is a major concern during the current COVID-19 pandemic (Bergwerk et al., NEJM, 2021), we believe that our findings are of significant public health interest. Our results will help to better assess the risk posed by the Mu variant for vaccinated, previously infected and naive populations.

Research available in bioRxiv (Sept. 7, 2021);

https://doi.org/10.1101/2021.09.06.459005 

Under-30s to be offered jabs from next week but variant makes decision on easing rules in England ‘more difficult’.  The new Delta variant of coronavirus appears to be about 40% more transmissible than the variant it has largely replaced, Matt Hancock has said, making government decisions about whether to ease restrictions in England on 21 June “more difficult”. Saying that under-30s in England will be called to begin vaccinations from next week, the health secretary confirmed it was still possible the reopening programme could be delayed or some rules kept in place. “We consider all options,” he told Sky News. The transmissibility of the Delta variant, first identified in India, has been seen as a central factor to the decisions over whether to remove most remaining restrictions in England in a fortnight, with the decision due to be made later this week. Estimates have said the Delta variant could be anywhere between 30% and 100% more transmissible than the so-called Alpha variant first identified in Kent. But asked for the latest information, Hancock gave a figure of 40%. “That means that it is more difficult to manage this virus with the new Delta variant,” he said. “But crucially, after two doses of vaccine we are confident that you get the same protection that you did with the old variant. So the good news is that the vaccine still works just as effectively.” It was, he said, still too early to decide what might happen on 21 June: “The prime minister and I and the team will be looking at all of the data over this week … The critical thing is to see whether the four tests we have set have been met.” Saying the Covid vaccination programme had “severed but not broken” the link between infection rates and hospitalisations, Hancock said adults under 30 would be able to seek first injections from next week.

The emergence of SARS-CoV-2 variants with enhanced transmissibility, pathogenesis and resistance to vaccines presents urgent challenges for curbing the COVID-19 pandemic. While Spike mutations that enhance virus infectivity may drive the emergence of these novel variants, studies documenting a critical a role for interferon responses in the early control of SARS-CoV-2 infection, combined with the presence of viral genes that limit these responses, suggest that interferons may also influence SARS-CoV-2 evolution. Here, we compared the potency of 17 different human interferons against 5 viral lineages sampled during the course of the global outbreak that included ancestral and emerging variants. Our data revealed increased interferon resistance in emerging SARS-CoV-2 variants, indicating that evasion of innate immunity is a significant driving force for SARS-CoV-2 evolution. These findings have implications for the increased lethality of emerging variants and highlight the interferon subtypes that may be most successful in the treatment of early infections.

Posted in bioRxiv (March 21, 2021):

 https://doi.org/10.1101/2021.03.20.436257 

New research shows that a specific change in the SARS-CoV-2 coronavirus virus genome, previously associated with increased viral transmission and the spread of COVID-19, is more infectious in cell culture. Research out today in the journal Cell shows that a specific change in the SARS-CoV-2 coronavirus virus genome, previously associated with increased viral transmission and the spread of COVID-19, is more infectious in cell culture. The variant in question, D614G, makes a small but effective change in the virus's 'Spike' protein, which the virus uses to enter human cells.

Bette Korber, a theoretical biologist at Los Alamos National Laboratory and lead author of the study, noted, "The D614G variant first came to our attention in early April, as we had observed a strikingly repetitive pattern. All over the world, even when local epidemics had many cases of the original form circulating, soon after the D614G variant was introduced into a region it became the prevalent form." Geographic information from samples from the GISAID COVID-19 viral sequence database enabled tracking of this highly recurrent pattern, a shift in the viral population from the original form to the D614G variant. This occurred at every geographic level: country, subcountry, county, and city. Two independent lines of experimental evidence that support these initial results are included in today's paper. These additional experiments, led by Professor Erica Ollmann Saphire, Ph.D., at the La Jolla Institute, and by Professor David Montefiori, Ph.D., at Duke University, showed that the D614G change increases the virus's infectivity in the laboratory. These new experiments, as well as more extensive sequence and clinical data and improved statistical models, are presented in the Cell paper. More in vivo work remains to be done to determine the full implications of the change.

The SARS-CoV-2 virus has a low mutation rate overall (much lower than the viruses that cause influenza and HIV-AIDS). The D614G variant appears as part of a set of four linked mutations that appear to have arisen once and then moved together around the world as a consistent set of variations. "It's remarkable to me," commented Will Fischer of Los Alamos, an author on the study, "both that this increase in infectivity was detected by careful observation of sequence data alone, and that our experimental colleagues could confirm it with live virus in such a short time."....

Original Study Published in Cell:

https://doi.org/10.1016/j.cell.2020.06.043

BA.2.86, nicknamed Pirola, causing concern among scientists because of fear it could be more transmissible. The latest Covid-19 variant, BA.2.86, appears to be spreading in the UK, health surveillance data suggests. The variant, nicknamed Pirola, has prompted concern among scientists because of the high number of mutations it carries, which raises the possibility that it could evade the immune system more easily or be more transmissible. In a briefing note on Friday, the UK Health Security Agency (UKHSA) said that an outbreak at a care home in Norfolk and other cases across the UK indicated there was likely to be community transmission of the strain, but said it was too early to judge the full extent of its spread. In an outbreak of Covid-19 in a care home in Norfolk at the end of August, 33 out of 38 residents tested positive for the virus, along with 12 members of staff, the UKHSA said. One resident needed hospital treatment but no deaths were reported. Laboratory tests later showed that 22 residents had the BA.2.86 variant, along with six staff.

The outbreak was “an early indicator” that the variant may be sufficiently transmissible to have an effect in close-contact settings, the UKHSA said, though it was too early to draw any conclusions about how BA.2.86 would behave in the wider UK population. Twenty-nine of the 33 residents at the care home who tested positive for Covid-19 have recovered, along with all members of staff, the UKHSA added. Dr Renu Bindra, the UKHSA incident director, said that while BA.2.86 had a “significant number of mutations” compared with other variants circulating, the data so far was “too limited to draw firm conclusions” about the impact this would have on the transmissibility or severity of the virus. “It is clear that there is some degree of widespread community transmission, both in the UK and globally, and we are working to ascertain the full extent of this,” she said. “In the meantime, it remains vital that all those eligible come forward to receive their autumn vaccine as soon as it is offered to them.” Some early lab-based evidence has eased initial concerns about the potential of BA.2.86 to cause a new global wave of infection, as happened with the emergence of Omicron.

A pre-print study, from researchers in China, found that BA.2.86 is not as efficient at infecting cells in the lab compared with other circulating Omicron subvariants. Another pre-print study from researchers in Sweden found only modest drops in how well serum from blood donors could neutralise BA.2.86 compared with other variants. The latest Covid-19 vaccine booster programme has been brought forward from October to September as a precaution against BA.2.86. The booster programme will begin in England on 11 September, with jabs offered first to residents of adult care homes and clinically vulnerable people, before it is extended to everyone in the UK aged 65 and above.

See also latest UK SARS-CoV-2 Surveillance Report (Sept. 4, 2023):

https://www.gov.uk/government/publications/investigation-of-sars-cov-2-variants-technical-briefings/sars-cov-2-variant-surveillance-and-assessment-technical-briefing-53 

Health risk of EG.5, which is related to Omicron subvariant, judged to be low but may drive larger wave of infections. A new strain of Covid-19 has been designated as a variant of interest by the World Health Organization, although the public health risk has been judged as low. The variant, known as EG.5 or “Eris”, is related to an Omicron subvariant called XBB.1.9.2, and is growing in prevalence globally, with countries including the UK, China and US among those affected. However, the WHO suggested the variant does not pose a particular threat. “Based on the available evidence, the public health risk posed by EG.5 is evaluated as low at the global level,” the agency said, adding that the risk appeared to be on a par with other circulating variants of interest. “While EG.5 has shown increased prevalence, growth advantage, and immune escape properties, there have been no reported changes in disease severity to date,” the WHO added....

At the end of March 2023, XBB.1.16, a SARS-CoV-2 omicron XBB subvariant, emerged and was detected in various countries. Compared to XBB.1.5, XBB.1.16 has two substitutions in the S protein: E180V is in the N-terminal domain, and T478K in the receptor-binding domain (RBD). We first show that XBB.1.16 had an effective reproductive number (Re) that was 1.27- and 1.17-fold higher than the parental XBB.1 and XBB.1.5, respectively, suggesting that XBB.1.16 will spread worldwide in the near future. In fact, the WHO classified XBB.1.16 as a variant under monitoring on March 30, 2023. Neutralization assays demonstrated the robust resistance of XBB.1.16 to breakthrough infection sera of BA.2 (18-fold versus B.1.1) and BA.5 (37-fold versus B.1.1). We then used six clinically-available monoclonal antibodies and showed that only sotrovimab exhibits antiviral activity against XBB subvariants, including XBB.1.16. Our results suggest that, similar to XBB.1 and XBB.1.5, XBB.1.16 is robustly resistant to a variety of anti-SARS-CoV-2 antibodies. Our multiscale investigations suggest that XBB.1.16 that XBB.1.16 has a greater growth advantage in the human population compared to XBB.1 and XBB.1.5, while the ability of XBB.1.16 to exhibit profound immune evasion is comparable to XBB.1 and XBB.1.5. The increased fitness of XBB.1.16 may be due to (1) different antigenicity than XBB.1.5; and/or (2) the mutations in the non-S viral protein(s) that may contribute to increased viral growth efficiency.

Published in bioRxiv (april 6, 2023):

https://doi.org/10.1101/2023.04.06.535883 

Significance

Abstract

Scientists are closely watching a new variant circulating in South Africa - but there are few clear answers.  The latest form is the most heavily mutated version discovered so far - and it has such a long list of mutations that it was described by one scientist as "horrific". The confirmed cases are mostly concentrated in one province in South Africa, but there are hints it may have spread further. Immediately there are questions around how quickly the new variant spreads, its ability to bypass some of the protection given by vaccines and what should be done about it. There is a lot of speculation, but very few clear answers. 

People infected with a variant first identified in South Africa are more likely to die than those infected with other variants.  People infected with the Beta coronavirus variant are more likely to need critical care and to die than are people infected with other variants1. The Beta variant, also known as B.1.351, was first identified in late 2020 in South Africa, where it sparked a second COVID-19 wave before spreading globally. Some evidence has suggested that severe cases of COVID-19 were more common during South Africa’s Beta-driven second wave than during its first wave, caused by the ancestral version of SARS-CoV-2. To determine whether the Beta variant is linked to increased severity, Laith Jamal Abu-Raddad, an infectious-disease epidemiologist at Weill Cornell Medicine—Qatar in Doha, studied infected people in Qatar in early 2021. During that period two variants were circulating: Beta and Alpha, which originated in the United Kingdom in 2020 and is also known as B.1.1.7. The team did not compare Beta with the Delta variant, which is now ripping through much of the world and which has also been linked to heightened severity.

People infected with Beta were 25% more likely than those infected with Alpha to develop severe disease , and around 50% more likely to require critical care, as well as 57% more likely to die. This fits with observations at the time, says Abu-Raddad. As Beta surged in Qatar, acute-care admissions doubled, and ICU admissions and deaths quadrupled. “It was very clear we were talking about a more severe variant,” he adds. The findings have not yet been peer reviewed. The study was small, but it is important because its conclusions stem from a careful comparison of the outcomes of infections with different variants in people with similar characteristics, such as age and sex, says Waasila Jassat, a public health medicine specialist at the National Institute for Communicable Diseases in Johannesburg, South Africa. She led a study2 published in July that found that people were around 30% more likely to die after hospitalization during South Africa’s second wave than in its first. Pinning down Beta’s severity will help researchers to anticipate its effects on health-care systems, Jassat adds. As the more-transmissible Delta variant spreads, Beta is now fading in many places where it was once dominant, including South Africa and Qatar. But Abu-Raddad notes that Beta seems to be more resistant to immunity generated by vaccines and previous infections than are other variants, including Delta, and it could begin wreaking havoc again. “We should never underestimate this pathogen.”

Research Cited Available as Preprint in medRxiv (August 4, 2021):

https://doi.org/10.1101/2021.08.02.21261465 

HANOI, Vietnam (AP) — Vietnam has discovered a new coronavirus variant that’s a hybrid of strains first found in India and the U.K., the Vietnamese health minister said Saturday. Nguyen Thanh Long said scientists examined the genetic makeup of the virus that had infected some recent patients, and found the new version of the virus.  Viruses often develop small genetic changes as they reproduce, and new variants of the coronavirus have been seen almost since it was first detected in China in late 2019. The World Health Organization has listed four global “variants of concern” – the two first found in the U.K. and India, plus ones identified in South Africa and Brazil. Long says the new variant could be responsible for a recent surge in Vietnam, which has spread to 30 of the country’s 63 municipalities and provinces. 

Vietnam was initially a standout success in battling the virus — in early May, it had recorded just over 3,100 confirmed cases and 35 deaths since the start of the pandemic. But in the last few weeks, Vietnam has confirmed more than 3,500 new cases and 12 deaths, increasing the country’s total death toll to 47. Most of the new transmissions were found in Bac Ninh and Bac Giang, two provinces dense with industrial zones where hundreds of thousands of people work for major companies including Samsung, Canon and Luxshare, a partner in assembling Apple products. Despite strict health regulations, a company in Bac Giang discovered that one fifth of its 4,800 workers had tested positive for the virus. In Ho Chi Minh City, the country’s largest metropolis and home to 9 million, at least 85 people have tested positive as part of a cluster at a Protestant church, the Health Ministry said. Worshippers sang and chanted while sitting close together without wearing proper masks or taking other precautions. Vietnam has since ordered a nationwide ban on all religious events. In major cities, authorities have banned large gatherings, closed public parks and non-essential business including in-person restaurants, bars, clubs and spas. Vietnam so far has vaccinated 1 million people with AstraZeneca shots. Last week, it sealed a deal with Pfizer for 30 million doses, which are scheduled to be delivered in the third and fourth quarters of this year. It is also in talks with Moderna that would give it enough shots to fully vaccine 80% of its 96 million people.

The new strain may be growing faster in some parts of the country, Health Secretary tells MPs. Health Secretary Matt Hancock said at least 60 different local authorities had recorded Covid infections caused by the new variant. He said the World Health Organization had been notified and UK scientists were doing detailed studies. He said there was "nothing to suggest" it caused worse disease or that vaccines would no longer work. He told MPs in the House of Commons that over the last week, there had been sharp, exponential rises in coronavirus infections across London, Kent, parts of Essex and Hertfordshire. "We've currently identified over 1,000 cases with this variant predominantly in the South of England although cases have been identified in nearly 60 different local authority areas. "We do not know the extent to which this is because of the new variant but no matter its cause we have to take swift and decisive action which unfortunately is absolutely essential to control this deadly disease while the vaccine is rolled out." 

RetroVirox offers a menu of cell-based antiviral services to evaluate experimental therapies and vaccines against coronaviruses, including SARS-CoV-2. The company offers in vitro testing with SARS-CoV-2 pseudovirions and with  live SARS-CoV-2 viruses to evaluate entry inhibitors, neutralizing antibodies, and antivirals against the novel coronavirus causative agent of COVID-19. Multiple viral strains are available for testing, including the most recent Omicron variants of concern (XBB.1.5, XBB.1.16, XBB.2.3.2, EG.5.1 JN.1, KP.2, and KP.3).

Pseudoviruses  coated with the viral spike (S) protein of SARS-CoV-2 are also used to recapitulate the mode of entry of the novel coronavirus. Over 50 spike mutant and variants are available as pseudoviruses. These assays can be used for the following purposes:

• To determine the neutralizing activity of therapeutic antibodies and antisera
• To test experimental COVID-19 vaccines using antisera from inoculated animals or humans
• To evaluate small-molecule and other entry inhibitors targeting the S viral protein, the ACE-2 viral receptor, or host proteases and other targets involved in SARS-CoV-2 viral entry

Assays with live replicating SARS-CoV-2, and milder forms of seasonal human coronaviruses (hCoV-OC43  and 229E) allow for the evaluation of inhibitors at all stages of the coronavirus life cycle. Additional Information about the coronavirus assays and many other cell-based antiviral assays offered at RetroVirox is available here. Request additional information by email at info@retrovirox.com