Variant EG.5 (ERIS)

I first noted that EG.5 (ERIS) was a rapidly rising variant July 11th on this substack. I stopped just short of saying it could become the dominant variant this fall because, frankly, the spike protein is not particularly remarkable relative to other variants. There are only 3 mutations in total in the spike protein and only one is in the receptor binding domain (F456L) which happens to be a mutation we’ve seen before in other virus variants. For example, BA.1.23, along with multiple other spike protein mutations contained F456L. However, BA.1.23, though it did try, was not awarded the “Goddess of Strife and Discord” aka ERIS title.

(Image Data: CDC, Image borrowed from: Dr.EricDing tweet)

In August the WHO released a report detailing their predictions for what we now call ERIS noting that it has ‘Moderate’ immune escape potential. The report notes that the F456L mutation reduces binding of some but not all antibodies raised against XBB.1.5 citing this pre-print. Frankly, I expected more of an exciting mutation set for the next dominant variant. The single mutation immune escape story possibly erroneously being relegated in my mind to the early days of the Alpha variant. The Alpha variant had more spike protein mutations than the original Wuhan variant, than ERIS does relative to XBB.1.5.

But why is ERIS so dominant and should we be worried?

I believe we are facing a perfect storm of conditions that will allow ERIS to become the dominant variant for the next two to three months. I don’t believe ERIS will be the dominant variant heading into the winter holidays. In an effort to be brief (an entire academic review could be written) here are the ones I believe are most significant:

• Infection Induced Antibody titer waning: Early July tends to be a low point in COVID test positivity meaning most people have not recently been infected (note reinfections can happen rapidly).

• Booster Shot Efficacy Waning: Antibody titers from booster shots also wane and the last booster shot was made available over 6 months ago.

• Moderate Immune escape: Although not complete antibody escape (and T cells will still recognize the virus and reduce illness severity) some antibody escape in combination with lower antibody levels is enough render most protection from initial infection negligible.

• Patterns of SARS-CoV-2 Spread: In our brief history with SARS-CoV-2 infections trend upwards starting just after the 4th of July with marked increases around the start of school, Thanksgiving, and the mid to late December holiday season. We are at the beginning of a period where test positivity rates have increased before.

In sum, we are currently facing a vaccine-virus mis-match combined with waning and virus spread increase leading to a gap in protection. The last booster was directed towards a significantly different virus from XBB.1.5 and thus even more different from ERIS. Therefore, it is likely that people who were recently infected with XBB.1.5 may briefly have better infection protection against ERIS until booster shots catch up.

In 2021 for a brief period in the Fall of 2021 vaccine waning combined with a new variant (Delta) showed up in the data as infection induced immunity being briefly superior to vaccine only immunity (vaccine + infection yielded the best protection). However, unvaccinated people generally had higher infection rates and most had been more recently infected than people had been vaccinated. The CDC detailed these findings in New York and California (MMWR link).

As ERIS levels climb we may again see this blip in the data until boosters catch up. I am as always very COVID cautious but now as cases are rising, my last booster was late last year and I have yet to experience infection (that I know of), but I am currently ramping up my personal protocols. New boosters are expected to be approved and released to the public by the end of September.

Should we worry? At the macro level ERIS is unlikely to cause significant hospitalization and death like we have seen with the Delta and Omicron variants. Deaths will increase, hospitalization will increase, this winter. However, I do not expect us to see tent hospitals and children being air-lifted across multiple states to find an open pediatric bed as we have in prior waves.

Short of having a crystal ball it’s difficult to say exactly how bad it will be. My best estimates are somewhere between where we are now as a low point and about 30-50% of the cases we saw with Omicron. I believe a lower percentage of positive cases, likely about half or fewer of what we saw with Omicron will be hospitalized. This is mostly because our T cells have no problem recognizing the ERIS variant and B cells can adapt rapidly to produce antibodies that will neutralize the virus. Note that all of these general predictions are ignoring influenza, RSV, and other viruses which increase in winter months.

At the personal level, I maintain avoiding infection in the first place is the best possible way to avoid complications and health issue that can arise from COVID infection and repeat infection. I am one of the few, but I am still masking. I do not eat indoors at restaurants, and recommend a high quality KN95, N95 or KF94 that fits your face well for indoor masking. For those that wonder, I wear a mask outdoors when in close proximity to people or in a crowd.

Forward Looking Technical Note: We know that the spike protein is not the only protein of interest in SARS-CoV-2. What has piqued my interest in the mutational set is that there are some potentially interesting changes in the N protein, ORF1a, and ORF10 proteins that either participate in virus replication and engage in direct suppression of immune responses. Changes in these proteins may make the virus replicate more efficiently and may suppress the innate immune response. Both of these can lead to relative increases in R-naught (Ro) or the number of people one person, on average, infects. Unfortunately that is not my area of research but if that is occurring, scientists will find it.