Science: Pre-exposure Antibody Prophylaxis Protects Macaques From Severe Influenza

BSL-3 – Credit CDC PHIL

#18,592

Although a handful of countries have arranged to purchase a limited quantity of H5Nx vaccine (see here, here, here, and here) - existing vaccines may not be a good match against any emerging `pandemic strain' of H5 - and even a well-matched vaccine might only provide limited protection against severe disease. 

Given the difficulties of mass producing (and deploying) billions of doses of a pandemic flu shot  (see Manufacturing Pandemic Flu Vaccines: Easier Said Than Done), most people won't be offered a flu jab during the first year (see Referral: SCI AM - A Bird Flu Vaccine Might Come Too Late to Save Us from H5N1).

While there are antivirals like Oseltamivir (aka Tamiflu), I.V. Peramavir, and the newer Baloxavir, all are in limited supply, must be administered early in the course of an illness, and - at best - can only reduce the severity and duration of symptoms (Clinical Inf. Dis.: Benefit of Early Oseltamivir Therapy for Adults Hospitalized with Influenza A: An Observational Study).

Add in the potential for (spontaneous or acquired) resistance, and the fact that we've had problems distributing these type of drugs during moderate-to-severe flu seasons, and it is easy to see why other approaches are needed. 

During the COVID pandemic a third option - monoclonal antibodies (mAbs) - were introduced late in 2020, and gained wider use in 2021.  For a time they were hailed as `game changers', but within a couple of years all had been rendered ineffective by changes to the virus (see FDA Withdraws EUA (Emergency Use Authorization) For Last COVID Monoclonal Antibody: Bebtelovimab).

Still, since mAbs can be used both as a treatment and a (short-term) prophylaxis, the could be quite handy during the opening months of any novel flu outbreak.  Front line personnel could potentially receive it as a preventative measure, and those critically ill might be treated with it (along with antivirals). 

One of the human mAbs that has been under investigation for years is MEDI8852, which binds to the HA gene of influenza A, allowing it to neutralize a broad spectrum of  subtypes (see 2017's  J.I.D. The Hemagglutinin A Stem Antibody MEDI8852 Prevents and Controls Disease and Limits Transmission of Pandemic Influenza Viruses).

Yesterday a research article was published in the Journal Science which detailed experiments performed at the University of Pittsburgh with MEDI8852 in preventing HPAI H5 infection in Macaques.  While most of this report is behind a pay wall, the University of Pittsburgh has published a summary press release.

First, the link to the report, followed by excerpts from the press release. I'll have a bit more after the break:

Pre-exposure antibody prophylaxis protects macaques from severe influenza
Masaru Kanekiyo , Rebecca A. Gillespie , Kristine Cooper, Vanessa Guerra Canedo , Priscila M. S. Castanha, Amarendra Pegu, Eun Sung Yang , Luke Treaster, Gabin Yun, [...], and Simon M. Barratt-Boyes +26 authorsAuthors Info & Affiliations
Science 30 Jan 2025 Vol 387, Issue 6733 pp. 534-541

Antibody Treatment Prevents Severe Bird Flu in Monkeys

Anastasia (Ana) Gorelova

1/30/2025

PITTSBURGH – A prophylactic antibody-based immune therapy protects monkeys against severe disease caused by H5N1 avian flu, University of Pittsburgh and NIH Vaccine Research Center researchers report today in Science.

The broadly neutralizing antibody, which recognizes a relatively stable region of the bird flu virus, is less prone to losing its efficacy than antibodies targeting influenza’s more mutation-prone structures. This feature ensures that the immune protection can withstand the possible emergence of virus variants, akin to the SARS-CoV-2 mutants that evolved during the COVID-19 pandemic, and provide lasting protection against a globally spreading airborne infection.

“This type of prevention can be very useful in controlling infection outbreaks and containing the bird flu pandemic,” said co-corresponding author Douglas Reed, Ph.D., associate professor of immunology at Pitt’s School of Medicine and the Center for Vaccine Research. “In our testing, the antibody performed beautifully. The antibody could be useful as a prophylactic of severe disease in vulnerable populations, and it also helped us establish the testing threshold for antibody levels in blood, which would be useful for judging the immune protection generated by a universal flu vaccine.”

(SNIP)

“This antibody is targeting a region that does not vary across different influenza viruses,” said co-corresponding author Simon Barratt-Boyes, Ph.D., professor of infectious diseases and microbiology at Pitt’s School of Public Health and immunology at Pitt’s School of Medicine. “Think about it as a tree – different species have different leaves and crowns, but tree trunks look very much the same. Similarly, the stalk region of the bird flu virus closely resembles the same structure of seasonal influenza, which makes it possible for stalk-targeting antibodies to provide universal protection.”

In a new study, monkeys pre-treated with a moderate dose of a broadly neutralizing MEDI8852 antibody were universally protected against severe disease and death. In addition to confirming the antibody’s efficacy in preventing serious adverse health outcomes, scientists were also able to establish its minimum serum concentration required for protection – a measurement useful for establishing the protective threshold of a potential universal flu vaccine.

The research sets the stage for the development of medical countermeasures against future influenza virus pandemics. Serum levels of MEDI8852 sufficient for protection remained stable for 8 to 12 weeks, suggesting that, if given early, it could protect first responders and others caring for patients at the beginning of an outbreak of H5N1. 

Masaru Kanekiyo, Ph.D., of the NIH Vaccine Research Center, also contributed to the study. Other authors of this research are affiliated with the NIH Vaccine Research Center, Pitt, UPMC, University of Georgia and AstraZeneca.

This research was supported by the Vaccine Research Center, an intramural division of the National Institute of Allergy and Infectious Diseases; and the National Institute of Allergy and Infectious Diseases (grants, R01AI154894 and UC7AI180311, and contracts 75N93021C00014 and HHSN261201500003)

Although animal studies have been promising, MEDI8852 remains an investigational drug, and has not been approved for clinical use. It could be employed during a pandemic under an EUA (Emergency Use Authorization), as were the COVID mAbs.

While we have some existing pharmacological options for treating and preventing novel flu, none are particularly robust. 

• Vaccines and mAbs may reduce the severity of illness, but many breakthrough infections are still expected.

• Antivirals - if given early enough - may reduce the severity and duration of symptoms, and may improve survival rates of some people. But are far from being a `cure'. 

• All of these drugs may have (usually mild or moderate) adverse effects (AEs), that may discourage their use.

• And timely access to these drugs - even in high resource regions - is likely to be a problem.  For the rest of the world, highly unlikely. 

Our first line of defense will - once again - rely heavily on NPIs (non-pharmaceutical interventions), like face masks, hand washing, ventilation, staying home while sick, and avoiding crowds.  

All reasons why there is still value in trying to prevent - or at least delay - the next pandemic.

ECDC: SARS-CoV-2 Variant Mutations Conferring Reduced Susceptibility to Antiviral Drugs and Monoclonal Antibodies

 
#17,542

Two summers ago the UK's SAGE (Scientific Advisory Group for Emergencies) on COVID released a series of detailed reports on the SARS-CoV-2 pandemic, and where they thought things might go from there.

Their concerns boiled down to three main areas:

1. The emergence of a much more severe variant
2. Decreasing vaccine effectiveness
3. The emergence of drug resistant variants

While their first `worst case' scenario has thankfully not occurred, the other two have.

A year ago a new Bivalent COVID Booster Shot was approved (which is now being updated again for XBB), and eight months ago the FDA Withdrew EUA (Emergency Use Authorization) For Last COVID Monoclonal Antibody: Bebtelovimab. 

Leaving antivirals like Paxlovid and Veklury and Lagevrio as the preferred treatment options for acute COVID.  But as COVID continues to evolve, these treatments are not guaranteed to remain effective.

Today the ECDC has released an 11-page technical report reviewing the currently available data on SARS-CoV-2 therapeutic monoclonal antibodies and antiviral drugs authorized for use in the EU/EEA.

As the following excerpt indicates, there are already mutations showing up in some variants that greatly reduce the effectiveness of our remaining armamentarium:

The mutations found in ORF1ab, namely nsp5:S144A, nsp5:Q189K, nsp5:H172Y, nsp5:E166A, and nsp5:F140A conferred moderate to high reduction in susceptibility to Paxlovid (nirmatrelvir/ritonavir), while nsp12:S861G conferred 25–99-fold reduction in susceptibility to Veklury (remdesivir) (Table 3).

This report will be primarily of interest to clinicians in the EU, but it is a reminder that COVID continues to evolve, and research on new therapeutics is essential. 

SARS-CoV-2 variant mutations conferring reduced susceptibility to antiviral drugs and monoclonal antibodies: a non-systematic literature review for surveillance purposes
Literature review
12 Jul 2023

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Antiviral drugs and monoclonal antibodies (mAbs), administered either separately or as combination therapy 'cocktails’, have provided a valuable tool for fighting COVID-19. Surveillance data, coupled with data on antiviral treatment susceptibility, can guide clinical decisions on selecting the best therapy for the patient.

Executive summary

The aim of this report is to provide a non-systematic literature review on the currently available data on SARS-CoV-2 therapeutic mAbs and antiviral drugs authorised for use in the European Union/European Economic Area (EU/EEA). In total, 258 publications on the four approved mAbs and 23 publications on antiviral drugs were analysed. 

• According to these studies, the ORF1ab mutations nsp5:S144A, nsp5:Q189K, nsp5:H172Y, nsp5:E166A, and nsp5:F140A conferred moderate to high reduction in susceptibility to Paxlovid (nirmatrelvir/ritonavir).

• The data indicated a highly reduced neutralisation capacity of Ronapreve (casirivimab/imdevimab) for all Omicron sub-lineages included in this report.

• The sub-lineages BA.1, BA.2, and BA.5 showed high reduction in susceptibility to Regkirona (regdanvimab).
  

• Xevudy (sotrovimab) showed high neutralisation efficacy against most SARS-CoV-2 variants, but moderate reduction in neutralisation activity for BA.2, BA.4, and BQ.1.1.

• Highly reduced neutralisation activity against the BQ.1 and BQ.1.1 sub-lineages was observed for Evusheld (tixagevimab/cilgavimab).

Monitoring the resistance of circulating new variants to mAb-based antiviral treatments is important for making decisions on whether some of the developed mAbs should be discontinued or different combinations of mAbs should be used. Neutralising susceptibility data are quite variable, leading to discordant findings among investigations. Therefore, adopting a global external standard for calibration would improve concordance across various tests and results could be provided in global units.

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SARS-CoV-2 variant mutations conferring reduced susceptibility to antiviral drugs and monoclonal antibodies - EN - [PDF-498.78 KB]

FDA Withdraws EUA (Emergency Use Authorization) For Last COVID Monoclonal Antibody: Bebtelovimab

A Radically Different COVID - Antigenic Diversity of SARS-CoV-2  

#17,146

In the summer of 2021, when many world leaders were optimistically touting the `imminent end of the pandemic' the UK's SAGE (Scientific Advisory Group for Emergencies) on COVID released a series of detailed reports on the SARS-CoV-2 pandemic, and where they thought things might go from there.

Their concerns boiled down to three main areas:

1. The emergence of a much more severe variant
2. Decreasing vaccine effectiveness
3. The emergence of drug resistant variants

While their first `worst case' scenario has thankfully not occurred, the other two have.  

Our COVID vaccines, which were once thought to be > 90% effective in preventing infections, now - with the emergence of newer Omicron variant(s) - are most useful in preventing severe illness (see ECDC: Interim Analysis of COVID-19 Vaccine Effectiveness in Healthcare Workers).  

The duration of their protection is also measured in months, not years as originally hoped. 

As a result, last July the FDA Recommended Adding BA.4/5 Spike Protein To Create A Bivalent COVID Booster Shot for this fall in the United States. While the results are still coming in, some evidence suggests these bivalent boosters may be more effective than their predecessors against Omicron.  

But how much, and for how long, remains to be seen. 

Similarly, our armamentarium of COVID treatments has withered in the 12 months since Omicron emerged.

• In January of this year we saw the FDA withdraw their EUAs on bamlanivimab and etesevimab (administered together) and REGEN-COV (casirivimab and imdevimab) (see FDA Removes Authorization For Two Monoclonal Antibody Therapies Due To Omicron).
• In March the FDA Limited Use Of Sotrovimab Monoclonal Antibody As Rising BA.2 Erodes Effectiveness.
• And three weeks ago (Nov. 10th) the FDA updated their COVID-19 Treatment Guidelines, warning:

The Centers for Disease Control and Prevention (CDC) has reported a rapid increase in the circulation of certain SARS-CoV-2 Omicron subvariants in the United States that are likely to be resistant to currently used anti-SARS-CoV-2 monoclonal antibodies (mAbs).1

The subvariants BQ.1 and BQ.1.1 are likely to be resistant to bebtelovimab,2 and the subvariants BA.4.6, BA.2.75.2, BA.5.2.6, BF.7, BQ.1, and BQ.1.1 are likely to be resistant to tixagevimab plus cilgavimab (Evusheld).

The anticipated loss of susceptibility is based on knowledge about amino acid mutations that confer resistance to anti-SARS-CoV-2 antibodies and on data from in vitro neutralization studies.3

Not unexpectedly, on Wednesday the FDA made it official; withdrawing their EUA from Bebtelovimab, the last remaining monoclonal antibody for COVID on the shelf. 

FDA Announces Bebtelovimab is Not Currently Authorized in Any US Region
 

[11/30/2022] The U.S. Food and Drug Administration today announced bebtelovimab is not currently authorized for emergency use in the U.S. because it is not expected to neutralize Omicron subvariants BQ.1 and BQ.1.1., according to data included in the Health Care Provider Fact Sheet.

Nowcast data from the Centers for Disease Control and Prevention published last week estimates that the combined proportion of COVID-19 cases caused by the Omicron BQ.1 and BQ.1.1 subvariants to be above 57% nationally, and already above 50% in all individual regions but one, and data shows a sustained trend of increasing prevalence across all regions. Given that a COVID-19 infection is likely to be caused by a non-susceptible SARS-CoV-2 variant, and consistent with the terms and conditions of the Letter of Authorization, bebtelovimab is not currently authorized for emergency use in any U.S. region at this time.

Eli Lilly and its authorized distributors have paused commercial distribution of bebtelovimab until further notice by the Agency. Additionally, the Administration for Strategic Preparedness and Response (ASPR) has paused the fulfillment of any pending requests under its Bebtelovimab Product Replacement Initiative.

The U.S. Government recommends all product be retained in the event that SARS-CoV-2 variants susceptible to bebtelovimab, which are currently circulating at lower prevalence, become more prevalent in the future in the United States. Retained product must be appropriately held in accordance with storage conditions detailed in the authorized Fact Sheet for Health Care Providers and the Letter of Authorization for bebtelovimab.

Health care providers should use other approved or authorized products that are expected to retain activity against BQ.1 and BQ.1.1 as they choose appropriate treatment options for patients, which include the following: 

• Paxlovid is authorized for the treatment of mild-to-moderate COVID-19 in adults and pediatric patients (12 years of age and older weighing at least 40 kg) with positive results of direct SARS-CoV-2 viral testing, and who are at high risk for progression to severe COVID-19, including hospitalization or death.
• Veklury is approved for the treatment of adults and pediatric patients (28 days of age and older and weighing at least 3 kg) with positive results of direct SARS-CoV-2 viral testing, who are not hospitalized and have mild-to-moderate COVID-19 and are at high risk for progression to severe COVID-19, including hospitalization or death.
• Lagevrio is authorized for the treatment of mild-to-moderate COVID-19 in adults with positive results of direct SARS-CoV-2 viral testing who are at high risk for progression to severe COVID-19, including hospitalization or death, and for whom alternative COVID-19 treatment options approved or authorized by FDA are not accessible or clinically appropriate.

In addition, COVID-19 convalescent plasma with high titers of anti-SARS-CoV-2 antibodies is authorized for the treatment of COVID-19 in patients with immunosuppressive disease or receiving immunosuppressive treatment, in inpatient or outpatient settings.

Individuals for whom COVID-19 vaccination is recommended should consider getting vaccinated with the primary series or, if vaccinated with the primary series, boosted with an updated bivalent vaccine when eligible to increase protection against the most serious consequences of COVID-19, including hospitalization and death.

For more information related to the therapeutic management of non-hospitalized patients with mild-to-moderate COVID-19, refer to the NIH COVID-19 Treatment Guidelines.

All treatment sites can continue ordering Paxlovid, Veklury, and Lagevrio by following the existing ordering processes and reporting procedures, as applicable.

FDA will continue to work with ASPR, the CDC, and the National Institutes of Health on surveillance of variants that may impact the use of the therapies authorized for emergency use. We will provide further updates and consider additional action as new information becomes available. 

While our pharmaceutical cupboard isn't entirely bare, treatment options have decreased markedly over the past year, and the remaining therapeutics are not effective or appropriate for everyone.  

And there is the real danger that future variants could render even more of these remaining treatments ineffective. 

Getting vaccinated, and staying boosted, however can go a long ways towards reducing the severity of COVID, while wearing a mask in public, practicing good hand hygiene, and avoiding crowds can substantially reduce your chances of getting infected. 

Considering what we've learned over the past year about the risks of reinfection (see Nature: Acute and Postacute Sequelae Associated with SARS-CoV-2 Reinfection), and our declining treatment options, prevention is still very much a useful strategy as we approach the 3rd anniversary of this pandemic. 

Preprint: Resistance of Omicron Subvariants BA.2.75.2, BA.4.6 and BQ.1.1 to Neutralizing Antibodies

A Radically Different COVID - Antigenic Diversity of SARS-CoV-2

#17,129

Next week will mark 1 year since the original announcement by South Africa's NICD on the spread of an emerging, and radically different COVID B.1.1.529 variant (dubbed VOC Omicron) - which, while `milder' than Delta - has proven itself to be far more transmissible. 

Much of its transmission advantage comes from Omicron's ability to evade prior immunity; acquired either from previous infection, from vaccination, or a combination of both. 

Vaccine `breakthrough' infections - which were once thought rare - are now quite common.  Although newer bivalent boosters appear to provide better protection (see Preprint: mRNA Bivalent Booster Enhances Neutralization Against 2 BA.2.75.2 and BQ.1.1), it is too soon to know how long that added protection will last. 

Nearly as concerning, we've seen a steady erosion in the number of monoclonal treatment options since the emergence of Omicron. 

• In January of this year we saw the FDA withdraw their EUAs on bamlanivimab and etesevimab (administered together) and REGEN-COV (casirivimab and imdevimab) (see FDA Removes Authorization For Two Monoclonal Antibody Therapies Due To Omicron).

• In March the FDA Limited Use Of Sotrovimab Monoclonal Antibody As Rising BA.2 Erodes Effectiveness.

• And on Nov. 10th the FDA updated their COVID-19 Treatment Guidelines, warning:

The Centers for Disease Control and Prevention (CDC) has reported a rapid increase in the circulation of certain SARS-CoV-2 Omicron subvariants in the United States that are likely to be resistant to currently used anti-SARS-CoV-2 monoclonal antibodies (mAbs).1

The subvariants BQ.1 and BQ.1.1 are likely to be resistant to bebtelovimab,2 and the subvariants BA.4.6, BA.2.75.2, BA.5.2.6, BF.7, BQ.1, and BQ.1.1 are likely to be resistant to tixagevimab plus cilgavimab (Evusheld).

The anticipated loss of susceptibility is based on knowledge about amino acid mutations that confer resistance to anti-SARS-CoV-2 antibodies and on data from in vitro neutralization studies.3

While the antiviral Paxlovid remains available, it is not appropriate for all patients (see CIDRAP report Many hospital COVID patients have factors that rule out Paxlovid), making the continued loss of monoclonal treatment options a concern. 

This loss of treatment options was among the possible scenarios discussed by the UK's SAGE (Scientific Advisory Group for Emergencies) on COVID, which released a series of reports over the summer of 2021.

 

With BQ.1.1 rising rapidly in the United States (we'll get a CDC Nowcast update later today), the following preprint - posted yesterday on the bioRxiv server - is particularly timely. 

Resistance of Omicron subvariants BA.2.75.2, BA.4.6 and BQ.1.1 to neutralizing antibodies

Delphine Planas, Timothee Bruel, Isabelle Staropoli, Florence Guivel-Benhassine, Francoise Porrot, Piet Maes, Ludivine Grzelak, Matthieu Prot, Said Mougari, Cyril Planchais, Julien Puech, Madelina Saliba, Riwan Sahraoui, Florent Femy, Nathalie Morel, Jeremy Dufloo, Rafael Sanjuan, Hugo Mouquet, Emmanuel Andre, Laurent Hocqueloux, Etienne Simon-Loriere, David Veyer, Thierry Prazuck, Helene Pere, Olivier Schwartz

doi: https://doi.org/10.1101/2022.11.17.516888

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Abstract

Convergent evolution of SARS-CoV-2 Omicron BA.2, BA.4 and BA.5 lineages has led to the emergence of several new subvariants, including BA.2.75.2, BA.4.6. and BQ.1.1. The subvariants BA.2.75.2 and BQ.1.1 are expected to become predominant in many countries in November 2022. They carry an additional and often redundant set of mutations in the spike, likely responsible for increased transmissibility and immune evasion.

Here, we established a viral amplification procedure to easily isolate Omicron strains. We examined their sensitivity to 6 therapeutic monoclonal antibodies (mAbs) and to 72 sera from Pfizer BNT162b2-vaccinated individuals, with or without BA.1/BA.2 or BA.5 breakthrough infection.

Ronapreve (Casirivimab and Imdevimab) and Evusheld (Cilgavimab and Tixagevimab) lost any antiviral efficacy against BA.2.75.2 and BQ.1.1, whereas Xevudy (Sotrovimab) remained weakly active. BQ.1.1 was also resistant to Bebtelovimab.

Neutralizing titers in triply vaccinated individuals were low to undetectable against BQ.1.1 and BA.2.75.2, 4 months after boosting. A BA.1/BA.2 breakthrough infection increased these titers, which remained about 18-fold lower against BA.2.75.2 and BQ.1.1, than against BA.1. Reciprocally, a BA.5 breakthrough infection increased more efficiently neutralization against BA.5 and BQ.1.1 than against BA.2.75.2. Thus, the evolution trajectory of novel Omicron subvariants facilitated their spread in immunized populations and raises concerns about the efficacy of most currently available mAbs. 

          (SNIP) 

In summary, we show here that the few convergent mutations present in the spike of BA.2 or BA.5 subvariants led to resistance to most of available therapeutic mAbs and strongly impaired the efficacy of vaccine-elicited antibodies.

Breakthrough infections in triply vaccinated individuals stimulate cross-neutralizing responses with distinct efficacy depending on the variant responsible for the infection. The evolution trajectory of the novel Omicron subvariants likely reflects their continuous circulation in immunized populations.

          (Continue . . . )

While the future course and impact of COVID are unpredictable, two weeks ago we saw another preprint out of China, warning that a new batch of Omicron subvariants (including BQ.1.1.10, BA.4.6.3, XBB, and CH.1.1) may possess even higher levels of immune escape.

They wrote:

Together, our results suggest current herd immunity and BA.5 vaccine boosters may not provide good protection against infection. Broad-spectrum SARS-CoV-2 vaccines and NAb drugs development should be highly prioritized, and the constructed mutants could help to examine their effectiveness in advance.

As long as this rapid-replacement cycle continues, it is going to be very difficult for vaccines and therapeutic development to keep up.

Preprint: Imprinted SARS-CoV-2 Humoral Immunity Induces Convergent Omicron RBD evolution

 

#17,097

In the summer of 2021, just months after the release of the mRNA vaccines, many world leaders were optimistically touting the `imminent end of the pandemic' (see UK PM: COVID Restrictions To End July 19th).

Tempering those expectations, the UK's SAGE (Scientific Advisory Group for Emergencies) on COVID released a series of detailed reports on the SARS-CoV-2 pandemic, and where they thought things might go from there. 

The most prescient of these reports was filed under Long term evolution of SARS-CoV-2, 26 July 2021, but this 15-page PDF was titled:

Can we predict the limits of SARS-CoV-2 variants and their phenotypic consequences?

As eradication of SARS-CoV-2 will be unlikely, we have high confidence in stating that there will always be variants. The number of variants will depend on control measures.

We describe hypothetical scenarios by which SARS-CoV-2 could further evolve and acquire, through mutation, phenotypes of concern, which we assess according to possibility. For this purpose, we consider mutations in the ‘body’ of the virus (the viral genes that are expressed in infected cells and control replication and cell response), that might affect virus fitness and disease severity, separately from mutations in the spike glycoprotein that might affect virus transmission and antibody escape.

We assess which scenarios are the most likely and what impact they might have and consider how these scenarios might be mitigated. We provide supporting information based on the evolution of SARS-CoV-2, human and animal coronaviruses as well as drawing parallels with other viruses.

Their `worst-case' scenario (#1 - a much more severe variant emerges) has, thankfully, not come to pass. But scenario #2 (decreasing vaccine effectiveness) and scenario #3 (Emergence of drug resistant variants) are both grim realities 15 months later.

  

While our pharmaceutical cupboard isn't entirely bare, treatment options have decreased markedly over the past 9 months (see FDA: The COVID-19 Treatment Guidelines Panel’s Statement on Omicron Subvariants and Anti-SARS-CoV-2 Monoclonal Antibodies), and newer variants could further erode our medical armamentarium against COVID.

As much as people want BA.5 to be COVID's last hurrah, SARS-CoV-2 continues to mutate and evolve, often generating new subvariants that are even better at evading existing immunity (either from vaccination, prior infection, or both) than previous iterations. 

All of which brings us to a new preprint out of China which finds that a new round of Omicron subvariants (including BQ.1.1.10, BA.4.6.3, XBB, and CH.1.1) show the highest level of immune escape seen to date. 

Not surprisingly, with thousands of subvariants vying for an increasingly smaller pool of susceptible hosts, the variants best able to evade existing immunity are the ones that flourish, while more susceptible variants do not. 

Immunity isn't a simple binary on/off switch, meaning that even low levels of immunity may be enough to keep some people from falling ill, and others out of the ICU. But the greater the degree of immune escape, the less effective vaccines, monoclonal antibodies, and immunity from past infection become. 

As the SAGE group envisioned, three years into this pandemic we find ourselves locked into a continually escalating arms race with the virus, with no end in sight. 

I've only posted the excerpt from the 44-page (and highly technical) preprint. Follow the link to read it in its entirety. 

Imprinted SARS-CoV-2 humoral immunity induces convergent Omicron RBD evolution
Yunlong Cao, Fanchong Jian, Jing Wang, Yuanling Yu, Weiliang Song, Ayijiang Yisimayi, Jing Wang, Ran An, Xiaosu Chen, Na Zhang, Yao Wang, Peng Wang, Lijuan Zhao, Haiyan Sun, Lingling Yu, Sijie Yang, Xiao Niu, Tianhe Xiao, Qingqing Gu, Fei Shao, Xiaohua Hao, Yanli Xu, Ronghua Jin, Zhongyang Shen, Youchun Wang, Xiaoliang Sunney Xie
doi: https://doi.org/10.1101/2022.09.15.507787
 

Preview PDF

Abstract

Continuous evolution of Omicron has led to a rapid and simultaneous emergence of numerous variants that display growth advantages over BA.5. Despite their divergent evolutionary courses, mutations on their receptor-binding domain (RBD) converge on several hotspots. The driving force and destination of such convergent evolution and its impact on humoral immunity remain unclear. 

Here, we demonstrate that these convergent mutations can cause striking evasion of neutralizing antibody (NAb) drugs and convalescent plasma, including those from BA.5 breakthrough infection, while maintaining sufficient ACE2 binding capability.

 BQ.1.1.10, BA.4.6.3, XBB, and CH.1.1 are the most antibody-evasive strain tested, even exceeding SARS-CoV-1 level. To delineate the origin of the convergent evolution, we determined the escape mutation profiles and neutralization activity of monoclonal antibodies (mAbs) isolated from BA.2 and BA.5 breakthrough-infection convalescents. 

Importantly, due to humoral immune imprinting, BA.2 and especially BA.5 breakthrough infection caused significant reductions in the epitope diversity of NAbs and increased proportion of non-neutralizing mAbs, which in turn concentrated humoral immune pressure and promoted convergent evolution. Moreover, we showed that the convergent RBD mutations could be accurately inferred by integrated deep mutational scanning (DMS) profiles, and the evolution trends of BA.2.75/BA.5 subvariants could be well-simulated through constructed convergent pseudovirus mutants. 

Together, our results suggest current herd immunity and BA.5 vaccine boosters may not provide good protection against infection. Broad-spectrum SARS-CoV-2 vaccines and NAb drugs development should be highly prioritized, and the constructed mutants could help to examine their effectiveness in advance.

Competing Interest Statement

X.S.X. and Y.C. are inventors on the provisional patent applications of BD series antibodies, which includes BD30-604 (DXP-604), BD55-5840 (SA58) and BD55-5514 (SA55). X.S.X. and Y.C. are founders of Singlomics Biopharmaceuticals. Other authors declare no competing interests.

CDC: Clarification On Reduced Effectiveness Of Monoclonal Antibodies Bamlanivimab & Etesevimab Against Some COVID Variants

#16,179

Although there are currently two monoclonal antibody regimens (sotrovimab or the combination of casirivimab and imdevimab) that have not shown any reduction in effectiveness against any of the known COVID variants, for some time there have been concerns over Eli Lilly's combo Bamlanivimab & Etesevimab, and at the end of August the FDA had limited its EUA (Emergency Use Authorization) to:

Despite this change notification, as of September 8th (see Bamlanivimab and Etesevimab Authorized States, Territories, and U.S. Jurisdictions) this mAb combo is still available in all U.S. states and territories, since it is still believed effective against the Delta variant which comprises more than 95% of call cases right now. 

But the concern is that - over time - if Delta gives way to some of the other VOIs and VOCs we've been watching,  treatment using Bamlanivimab & Etesevimab could be less effective. 

On Friday the CDC emailed out a COCA NOW newsletter that inadvertently left the impression that the Delta Variant might also evade this mAb treatment.  At this time, there is only a cautionary note on mAbs and Delta which reads;  Potential reduction in neutralization by some EUA monoclonal antibody treatments 7, 14

Overnight the CDC sent out the following email clarification. 

COCA NOW Clarification COCA Memo: Monoclonal Antibodies Bamlanivimab and Etesevimab May Be Less Effective for Treating Cases of COVID-19 Caused by SARS-CoV-2 Variants

The recent COCA NOW : Monoclonal Antibodies Bamlanivimab and Etesevimab May Be Less Effective for Treating Cases of COVID-19 Caused by SARS-CoV-2 Variants COCA notification released September 10, 2021 highlighted changes made to CDC’s Variant Classification and Definitions webpage, which primarily focused on updates to Substitutions of Therapeutic Concern. These updates contained accurate information, but unintentionally indicated a possible cause for concern that this combination monoclonal antibody product was not effective against infections with the SARS-CoV-2 Delta variant.

CDC has no evidence at present that Delta variants circulating in the United States carry mutations than might confer resistance to this drug.

The information provided in the Substitutions of Concern for SARS-CoV-2 Monoclonal Antibody Therapies is based on laboratory data provided in the Fact Sheet for Health Care Providers for EUA of Bamlanivimab and Etesevimab, which indicates no change in susceptibility to bamlanivimab and etesevimab for the Delta variants. As such, clinical recommendations have not changed.

Clinicians seeking advice on the use of monoclonal antibody products authorized for emergency use in the United States for the treatment and prevention of SARS-CoV-2 should consult the NIH COVID-19 Treatment Guidelines.

Lest anything think this reduction in mAb effectiveness against some variants is a new discovery, we've been discussing it for months (see here, here, and here). The CDC's latest update (Sept 11th) to their SARS-CoV-2 Variant Classifications and Definitions webpage advises:

Treatment considerations for healthcare providers

Substitutions of Concern for SARS-CoV-2 Monoclonal Antibody Therapies

In the United States, there are three anti-SARS-CoV-2 monoclonal antibody treatments with FDA Emergency Use Authorization (EUA) for the treatment of COVID-19: bamlanivimab plus etesevimab, casirivimab plus imdevimab, and sotrovimab.

CDC’s national genomic surveillance program identifies new and emerging SARS-CoV-2 variants to determine implications for COVID-19 diagnostics, treatments, or vaccines approved or authorized for use in the United States. Sequences with similar genetic changes are grouped into lineages, and multiple lineages can have the same substitutions. For example, the E484K substitution is found in lineages B.1.351, P.1, B.1.526, and many others. Genomic surveillance efforts provide the capability to detect viruses that have reduced susceptibility to treatments more quickly.

Reduced susceptibility of SARS-CoV-2 to sotrovimab or the combination of casirivimab and imdevimab has not been reported. In laboratory studies, SARS-CoV-2 variants that contain certain substitutions in the spike protein cause a reduction in susceptibility to the combination of bamlanivimab and etesevimab*. These include the following individual or combinations of substitutions:

• L452R
• E484K
• L452R and E484Q
• K417N, E484K, and N501Y
• K417T, E484K, and N501Y
• K417N, L452R, and T478K
• R346K, E484K, and N501Y

* For some substitutions or combination of substitutions, the reduction in susceptibility is modest, and the clinical implications of this modest decrease are not known at this time. Clinicians seeking advice on the use of monoclonal antibody products authorized for emergency use in the United States for the treatment and prevention of SARS-CoV-2 should consult the NIH COVID-19 Treatment Guidelines.

The data below show the national and regional unweighted proportions of SARS-CoV-2 that contain the individual or combinations of spike protein substitutions listed above. As new data become available, additional substitutions may be added below. The national and regional proportions provided below will be updated weekly.

Among the variants listed by the CDC which appear to evade the bamlanivimab and etesevimab mAb treatment are:

• VOC Beta - Significantly reduced susceptibility to the combination of bamlanivimab and etesevimab monoclonal antibody treatment,7 but other EUA monoclonal antibody treatments are available 14
• VOC Gamma - Significantly reduced susceptibility to the combination of bamlanivimab and etesevimab monoclonal antibody treatment,7 but other EUA monoclonal antibody treatments are available 14
• VOI Eta - Potential reduction in neutralization by some Emergency Use Authorization (EUA) monoclonal antibody treatments 7, 14
• VOI Iota - Reduced susceptibility to the combination of bamlanivimab and etesevimab monoclonal antibody treatment; however, the clinical implications of this are not known.7 Alternative monoclonal antibody treatments are available.14
• VOI Kappa - Potential reduction in neutralization by some EUA monoclonal antibody treatments 7, 14

Rapid evolution is a virus's best friend, and our worst enemy, during a pandemic. While it can sometimes attenuate a virus over time - so far with COVID - it has only made it more formidable.

Viruses have managed to exist for hundreds of millions of years because they are able to adapt to an ever-changing, and often hostile, environment.

An attribute our species would do well to emulate.