A summary of presentations from the weekly Summit partner webinars
April 21, 2022 – The latest Summit summary
- Flu Surveillance Update – Alicia Budd (CDC)
- SARS-CoV-2 Surveillance Update and Variant Analysis – David Wentworth (CDC)
Flu Surveillance Update – Alicia Budd (CDC)
Influenza Virologic Surveillance – U.S., 10/3/21–4/9/22:
Flu activity measured by percent of specimens tested positive in clinical labs is continuing to increase. Nationally, most of the regions are seeing an increase, however the degree of increase varies depending on location.
The U.S still has predominately influenza A H3N2 viruses belonging to the 3C.2a1b clade and the 2a.2 subclade, which is what has been circulating all season. There have been a few additional viruses tested, but influenza A H3N2 viruses are found to be not antigenically similar to the vaccine viruses. The antigenic similarity of the influenza B (Victoria) viruses is still higher than that of the influenza A viruses.
There has not been any antiviral resistance identified so far in the more than 800 viruses tested. There is one influenza A H3 virus with decreasing susceptibility to Baloxavir, but that is the only virus that’s been tested so far this season that has shown any reduced susceptibility to the antivirals.
Outpatient Visits for Respiratory Illness, Reported by the U.S. Outpatient Influenza-like Illness Surveillance Network (ILINet): Influenza-like illness (ILI) refers to someone who has a fever and cough or sore throat and could be caused by a number of respiratory viruses, including flu and SARS-CoV-2. The percent of visits has been slowly increasing since the middle of February, but still remains below the national baseline. The increase is being driven primarily by children and young adults.
ILI Activity Level, Determined by Data Reported to ILINet, Week ending April9, 2022 (Week 14): During week 14, there has been minimal outpatient respiratory activity, but there are some areas in the south-central and northeast parts of the country that are seeing moderate and high levels of activity. Flu is contributing to these levels, but respiratory illness could be caused by a number of viruses including RSV and COVID-19. The contribution of each varies by location. These hot spots typically have quite a bit of flu activity but also other virus activity.
Percent of Long-Term Care Facilities (LTCF) with at least One Confirmed Influenza Case among Residents, Reported to CDC’s National Healthcare Safety Network (NHSN), National Summary, 10/4/21–4/9/22: The number of LTCF reporting at least one flu positive case among their residents has been slowly increasing since February.
Influenza hospitalizations in the U.S.: HHS Protect shows the number of new admissions to hospitals that have a positive influenza test, which has been increasing since February. The cumulative influenza-associated hospitalization rate from FluServNet shows that flu activity is higher than the 2011–12 season, which was the mildest pre-COVID-19 flu season since the FLuServNet system began in 2005.
Influenza-related mortality data, U.S.: The percentage of death certificates that list pneumonia, influenza, or COVID-19 (PIC) as the cause of death continues to decrease but it remains just slightly above the epidemic threshold. Even with the decrease in COVID-19 activity, the flu contribution to this mortality is still quite small. There have been 19 pediatric deaths this season, all of which tested positive for influenza A H3N2 viruses.
International Influenza Activity, Number of Influenza Positives Reported to WHO’s FluNet, 10/2018–4/9/22: Flu positive activity reported to WHO shows that influenza A H3N2 is predominate worldwide except in China where influenza B (Victoria) is the dominate virus. In both hemispheres activity is increasing after the dip in January, but numbers remain lowers than where they were pre-COVID-19.
Other Respiratory Virus Activity
- COVID Data Tracker Weekly Review
- COVID Data Tracker
- National Respiratory Virus Surveillance System (NREVSS)
Highly Pathogenic Avian Influenza (HPAI) A(H5N1): Current Situation in the U.S. as of April 9 2022
CDC is continuing to get reports of HPAI H5N1 in both wild and commercial poultry and backyard flocks. Thirty-two states have detected the virus in wild birds and 29 states with detected virus in commercial poultry/backyard flocks.
There have not been any human cases documented in the U.S. at this time and the threat to the general public is low. Risk to poultry workers, outbreak responders and waterfowl hunters may be increased as wild bird and poultry outbreaks continue, which may lead to a human case in the U.S. It is safe to eat properly handled and cooked poultry.
For more information:
- CDC: Avian Influenza Current Situation Summary
- USDA: 2022 Detections of Highly Pathogenic Avian Influenza
Are the increased flu cases we are seeing in the season due to the reduction in mask wearing?
I wouldn’t be surprised if this is impacting part of this. We don’t have a way to tell specifically, but where there is flu circulating and people have stopped wearing masks, it’s easier for flu to take a foothold.
At this point in the season influenza B is typically showing up, but this year it’s influenza A H3N2. Why?
We often see a late season surge in influenza B activity, however not always. Just before the pandemic influenza B showed up before influenza A.
When there is an H5N1 outbreak, are farmers killing their birds or are they left to die?
They are being depopulated.
SARS-CoV-2 Surveillance Update and Variant Analysis – David Wentworth (CDC)
David Wentworth PhD, Co-Lead, COVID-19 Laboratory and Testing Task Force, Director, WHO Collaborating Center for Surveillance, Epidemiology and Control of Influenza, Chief, Virology Surveillance and Diagnosis Branch, Influenza Division, CDC gave a presentation SARS-CoV-2 surveillance and variant analysis. VIEW PRESENTATION SLIDES
The SARS-CoV-2 surveillance system is used to identify and track variants circulating both nationally and globally, conduct risk assessment through virus characterization, report data, and use data to inform the SARS-CoV-2 Interagency Group (SIG) to make recommendations to leadership for decision making. The surveillance systems that are in use are designed to be a genotype to phenotype throughput system. They offer contract sequencing to expand the data publicly, National SARS-CoV-2 Strain Surveillance (NS3) System and enhanced surveillance to generate sequence data and characterization for genotype and phenotype analysis, and continued analysis of viral genomic sequences through GISAIS/GenBank). Occasionally variants are identified by sequence analysis but there are no specimens available in the U.S. The solution to this is to engineer recombinant SARS-Co-2 variants by reverse genetics.
From January 23, 2022–April 15, 2022, the first major variant of SARS-CoV-2 was S-D614G which caused a large wave of cases. Then Alpha variant emerged which caused a small rise in the spring/summer of 2021, however not as high as the S-D614G or the Delta variant. The most recent variant, Omicron (BA.1.1.529), caused the largest spike in cases in early 2022.
National SARS-CoV-2 Genomic Surveillance Map shows which variants caused peaks in cases. There are three primary data sources for this system: NS3, commercial sequencing laboratories, and supporting state, territorial, local, and tribal health departments. Additional partners include universities and SARS-CoV-2 Sequencing for Public Health Emergencies Response, Epidemiology, and Surveillance (SPHERES) Consortium.
Changing Landscape of Circulating Variants Map shows the weekly proportion estimates of the variants. The Alpha variant peaked around April/May 2021 but didn’t displace other variants, then Gamma showed up in late spring/early summer 202. Beta variant came around the same time as Gamma, but never really got a foothold in the U.S. The large Delta wave displaced all of the other variants in summer of 2021 into the end of the year. Following Delta came Omicron which displaced nearly all other variants. Omicron was the most fit of the virus variants so far.
Nowcast is a model that estimates more recent proportions of circulating variants and enables timely public health action. To compensate for the time lag in sequencing from test swabs, CDC has a multinominal logistic regression model that shows predicted proportion at 95% prediction interval. This week, the Omicron (BA1.529) lineages make up 100% of the variants circulating in the U.S., with BA.2 representing 75% of the lineage. The new variant BA.2.12.1, which is a sub lineage of BA.2, represents 19% of the Omega lineage. The BA.1.1 lineage is at about 6%, however at one point in time this lineage represented the majority of the lineages of the Omicron variant.
See: Variant Proportions
The SARS-CoV-2 spike protein can differentiate one variant from another. This protein is a long molecule which gives the SARS-CoV-2 virus the corona (crown) appearance; the protein has two domains: S1 and S2. The S1 domain contains the receptor binding protein and a subdomain called the receptor binding domain (RBD) which is responsible for transmission and pathogenesis due to its ability to impact host range and tissue tropism. The S2 domain is part of molecular machine that’s responsible for fusion of the viral envelope with the host cell membrane. The spike protein is also important as a target for neutralizing antibodies against the virus.
Variants can be isolated and propagated and identified through genetic sequencing and titration. They can also be antigenically characterized with neutralization assays and comparative reactivity with antisera . Subsets of the viruses of interest can be used for in vitro replications in various cell types and in vivo studies can be constructed on a small number of animals to study transmission/pathogenesis and immune protection. Viruses can be created by recombinant approaches that can be then be used to test antigenicity, replication fitness, and pathogenicity/transmissibility.
The Wuhan-like virus (614D) that swept the globe before all other variants was very susceptible to neutralization. The Alpha variant (B.1.1.7) had around the same level of susceptibility to neutralization. All other variants are around 2–3 fold less susceptible in comparison until Omicron, which was much more resistant to neutralization with antibody from 614D.
Omicron has substitutions, insertions, and deletions to its spike protein all focused in the RBD region where neutralizing antibodies are most effective. The changes in multiple epitopes anticipate reduced neutralization by therapeutic antibodies and polyclonal antibodies induced by natural infection or vaccination.
Many of the variants are able to be neutralized, similar to the original Wuhan-like virus (614D), which contains the antigen used in the vaccine. The Beta variant showed a six-fold reduction compared to 614D, but Omicron showed a 38-fold reduction compared to 614D. Omicron recombinant reporter virus shows significant escape from neutralization using Focus Reduction Neutralization Test (FRNT).
Before a vaccine boost, the geometric mean titer (GMT) of Omicron (BA.1.1.529) was 34-fold reduced compared to 614D. After getting a booster dose of vaccine, antibody titer against Omicron was similar to the pre-boost titer of 614D, with only a 19-fold reduction compared to 614D. This demonstrates why boosting is helpful even against a very antigenically different virus. Even though Omicron titer is lower than the 614D titer post-boost, the boosting is increasing the titer levels significantly.
How will the sequence data for SARS-CoV2 be used for COVID-19 vaccine recommendations?
The sequence data shows the phenotypic characterization and allows us to see what is circulating. Some changes to the variants are silent but trackable by genetics. What really matters in terms of making the vaccines are the phenotypic changes (not the genetic changes) to the spike protein which is what the vaccine is targeting. These changes most influence what will go into the vaccine.
Can you talk more about what the challenges are for updating the vaccine strains for SARS-CoV-2 relative to flu?
For the flu there is a clear regulatory path for how we substitute antigens and that doesn’t require large clinical studies since we already understand flu characteristics and the vaccine safety profile. There are flu collaborating centers that work together across the globe that are sharing reagents and comparing data. These entities gather in Geneva twice a year to go over data on which variants of the flu to include in the vaccines.
With SARS-CoV-2, the virus didn’t change much initially, but once variants appeared, the changes occurred rapidly and displaced each other in a matter of months. There is still a lot to learn with this virus. There isn’t the track record that we have with the flu. We don’t have all of the pieces of the puzzle involved in the strain update and how the strain will affect the immune response.
There is a committee at WHO called Technical Advisory Group on COVID-19 Vaccine Composition which is a large group of experts that periodically reviews the evidence and analyses the implications of emerging variants of concern and the performance of the vaccines. CDC and NIH are also contributing to the data. All of these go into the making of a system that we can use to update antigens to positively impact vaccines.
We hear about some of the manufacturers doing their own work with variant-specific vaccines to replace the original vaccine. Where does that decision process lay currently? And is there a strain change vaccine currently being studied?
The decision process is country-specific and similar to that of the flu. WHO SAGE committee will recommend an update to a particular influenza virus subtype and that recommendation will go to the FDA’s VRBPAC committee which will make the official decision on which vaccine we will use in the U.S. SARS-CoV-2 manufactures are entitled to making potentially better vaccines. The infrastructure for making changes to influenza vaccine strains is being used for discussions about SARS-CoV-2 viruses and vaccine strains.
The 2022 Influenza Vaccine meeting, What’s Up with Flu in ’22! Surveillance, Vaccines, Policy, and Communications Last Year and Next, will be held virtually on May 19, 2022, from 2:00–4:45 p.m. (ET). Pre-meeting registration is required by 5:00 p.m. (PT)/8:00 p.m. (ET) on May 18, 2022, to attend. For more information and to register, visit: https://www.izsummitpartners.org/2022-naiis/.