Virus World

Following the emergence of SARS-CoV-2 in China in late 2019 a number of variants have emerged, with two of these – Alpha and Delta – subsequently growing to global prevalence. One characteristic of these variants are changes within the Spike protein, in particular the receptor binding domain (RBD). From a public health perspective these changes have important implications for increased transmissibility and immune escape; however, their presence could also modify the intrinsic host-range of the virus. Using viral pseudotyping we examined whether the variants of concern (VOCs) Alpha, Beta, Gamma and Delta have differing host ACE2 receptor usage patterns, focusing on a range of relevant mammalian ACE2 proteins. All four VOCs were able to overcome a previous restriction for mouse ACE2, with demonstrable differences also seen for individual VOCs with rat, ferret or civet ACE2 receptors, changes which we subsequently attribute to N501Y and E484K substitutions within the Spike RBD.

Preprint Available in bioRxiv (Nov. 24, 2021):

https://doi.org/10.1101/2021.11.23.469663

And what that tells us about the pandemic. Like any virus, SARS-CoV-2 has been mutating constantly since the beginning of the pandemic. Until November 2020, though, that didn’t seem to matter. That’s when scientists in the United Kingdom noticed an alarming change: The virus had mutated in a way that made it more transmissible. Within a month, similar reports were emerging from places around the world. Suddenly, it seemed the virus was changing at an alarming rate. SARS-CoV-2 hasn’t actually been mutating faster, though. Instead, by letting it spread around the world, we’ve just given it more and more opportunities to mutate as it replicates. The result is that after countless random mutations, there are signs that the virus is beginning to adapt to our natural defenses. And because it’s completely normal for a virus to change over time, we shouldn’t expect it to stop. The only real way to stop those changes is to stop giving the virus so many opportunities.

Click on this direct link to watch the video:

https://youtu.be/Ha6yUxze1vk 

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 

GAITHERSBURG, Md., June 11, 2021 /PRNewswire/ -- Novavax, Inc. (Nasdaq: NVAX), a biotechnology company developing next-generation vaccines for serious infectious diseases, today announced preclinical and clinical data on the company's original recombinant protein COVID-19 vaccine candidate, NVX-CoV2373, and for a new vaccine directed against the SARS-CoV-2 Beta (B.1.351) variant, which was originally identified in South Africa. The data show that the vaccines demonstrated strong immunogenicity and protection against both the Alpha (B.1.1.7) variant, which was originally identified in the United Kingdom, and the Beta (B.1.351) variant as well as the original SARS-CoV-2 in animal and human studies. A preprint of the manuscript, 'Immunogenicity and In vivo protection of a variant nanoparticle vaccine that confers broad protection against emerging SARS-CoV-2 variants,' is available at bioRxiv.org and has been submitted for peer review. "While current vaccines are effective against selected SARS-CoV-2 variant strains, newly emerging variants are also being identified that have the ability to overcome vaccine induced immunity," said Matthew Frieman, PhD, Associate Professor of Microbiology and Immunology at the University of Maryland School of Medicine, who collaborated on these studies. "This work demonstrates that variant vaccines that protect against these newly emerging variants have the potential to be highly effective and may produce broader protection against variants we know of and those that will arise in the future. Clinical trials will provide further evidence on the effectiveness of variant vaccines."  The studies compared the Beta (B.1.351)-directed vaccine to Novavax' prototype vaccine candidate as standalone, in combination, and as heterologous prime boost vaccine. The findings show a broad array of cellular and humoral responses in animal models against all virus strains evaluated. The Alpha (B.1.1.7) and Beta (B.1.351) variant strains have created public health concerns due to increased transmission rates and lower efficacy of current vaccines seen against Beta (B.1.351). "These data suggest that not only could one booster dose of this variant-directed vaccine potentially provide a robust, protective immune boost after vaccination against the original SARS-CoV-2 virus, but also the potential to provide broad protection against various virus strains if used as a primary vaccine regimen," said Gregory M. Glenn, M.D., President of Research and Development, Novavax. "This broad immune coverage is vital to controlling the pandemic as variants of concern continue to emerge worldwide that could jeopardize the protection created through ongoing COVID-19 vaccination efforts."

Study 1: Immunogenicity and Protection in Mice

Mice were immunized with NVX-CoV2373 or rS-B.1.351 alone, in combination, or as a heterologous prime boost. Mice vaccinated with any of the four regimens displayed elevated antibody titers against both the original and Beta (B.1.351) spike. Heterologous or bivalent vaccination is highly immunogenic against the prototype spike compared to monovalent approaches, while immunization with monovalent rS-B.1.351 or bivalent spike resulted in the highest anti-B.1.351 spike IgG titers among regimens tested.

Additionally, mice immunized with rS-B.1.351 alone produced elevated neutralizing antibody titers to the Alpha (B.1.1.7) and Beta (B.1.351) strains compared to titers upon immunization with the prototype-directed strain. Titers were similar in the heterologous and bivalent vaccine groups. Antibodies produced after vaccination with rS-B.1.351 inhibited binding between human angiotensin converting enzyme-2 receptor (hACE2) and the variant spike or original spike to the same degree. This indicates that rS-B.1.351 can efficiently protect "backward" against original SARS-CoV-2 strains. In contrast, NVX-CoV2373 was less efficient at protecting "forward" against the Beta (B.1.351) variant strain. Whether immunized with prototype vaccine or rS-B.1.351 alone, in combination, or as a heterologous prime boost, mice were protected when challenged with live Alpha (B.1.1.7) or Beta (B.1.351) variant strains of SARS-CoV-2.

Study 2: Anamnestic Response in Baboons

A cohort of baboons that were originally immunized with prototype vaccine were boosted approximately one year later with one or two doses of rS-B.1.351. Seven days after the first rS-B.1.351 boost, those that originally received adjuvanted prototype-directed vaccine exhibited a strong immune response, with anti-Spike IgG titers that were higher than the peak immune response observed during the primary immunization series. The rS-B.1.351 boost elicited comparable antibody titers against original and rS-B.1.351 spike. Further, the same cohort exhibited a strong neutralizing response to Alpha (B.1.1.7) and Beta (B.1.351) strains and hACE2-inhibiting antibody response following the boost, despite having undetectable titers before the boost. High neutralizing antibody titers were observed seven days post-boost, demonstrating "a robust, durable antibody response even one year after the primary vaccination series." These results suggest that one dose of a variant-directed vaccine may be sufficient for boosting regimens after previous immunization with a COVID-19 vaccine based on the original spike strain.

Study 3: Robust Antibody Response in Humans

NVX-CoV2373 is currently being studied in multiple clinical trials, including in locations where Alpha (B.1.1.7) and Beta (B.1.351) variant strains are widespread. Thirty randomly selected human serum samples from Phase 2 clinical trial participants after their second dose of the vaccine were assayed. The sera were analyzed for their ability to neutralize Alpha (B.1.1.7) and Beta (B.1.351) strains. The trial participants' sera demonstrated a neutralizing capacity of the Alpha (B.1.1.7) strain equal to NVX-CoV2373, with a modest reduction in neutralizing capacity against the Beta (B.1.351) strain. These data support the development and production of a Beta (B.1.351) targeted vaccine, which also demonstrated to be efficient at protecting mice against Beta (B.1.351) and to induce a strong response in primates originally immunized with NVX-CoV2373. Furthermore, the data support that a booster vaccine containing a variant strain could both increase antibody levels as well as broaden coverage. Novavax expects to initiate further clinical testing of rS-B.1.351 in the fall of 2021....

See bioRxiv (June 9, 2021):

https://doi.org/10.1101/2021.06.08.447631