Thread by @jeffgilchrist

Novavax Fall 2023 Vaccine Booster Update

Novavax presented at the June 15th FDA VRBPAC meeting to provide neutralization results from testing with various combinations of the original vaccine, BA.5, XBB.1.5 and XBB.1.16 boosters. This thread will highlight the presentation.🧵1/

An unrolled one-page web view for this long thread that may be easier to read or share can be found here ( ). 2/

https://twitter.com/jeffgilchrist/status/1678356489449140226

You can watch the Novavax presentation here ( ) and download the Novavax slides here ( https://t.co/ztwfYM0ScF ). 3/youtube.com/live/gBOyPREXG…
fda.gov/media/169540/d…

Novavax shows that all boosting regimens including multiple mRNA doses, mRNA+bivalent, mRNA+Novavax and multiple Novavax doses have low neutralization against the more recent XBB.1 variant (which is a recombination of two BA.2 based variants). 4/

Neutralization levels ranged from 72 to 162 GMT with XBB.1 compared to 5,818 to 23,201 GMT with the original variant. Novavax recommends that vaccines should be updated to a more recent strain to provide better immune response to currently circulating variants. 5/

Vaccinating mice with 2 doses of various monovalent (1 variant) vaccines. As similarly seen in humans, 2 doses of the original variant vaccine in mice had low neutralization levels (50 GMT) with XBB.1.5 "Kraken" and XBB.1.16 "Arcturus" variants. 6/

Two doses of XBB.1.5 vaccine had the highest neutralization levels against XBB.1.5 (5,354) then XBB.1.16 (3,915) with lower but significant neutralization against somewhat older variants such as BA.5, BQ.1.1 and CH.1.1. 7/

The XBB.1.16 specific vaccine had even higher levels of neutralization against both XBB.1.16 and XBB.1.5 compared to the XBB.1.5 vaccine but lower levels against BA.5 and BQ.1.1. 8/

You can see just how different the XBB family of variants are from the original variant as both the XBB.1.5 and XBB.1.16 specific vaccines now have low neutralization to the original variant, while the original vaccine is similarly low for XBB variants. 9/

Novavax compared 2 doses of monovalent XBB.1.5 with 2 doses of bivalent (Original + XBB.1.5) vaccine. The monovalent vaccine induced much higher neutralization responses to XBB.1.5 (4,554) and XBB.1.16 (4,156) compared to the bivalent to XBB.1.5 (981) and XBB.1.16 (2,168). 10/

Although the bivalent vaccine induced neutralization to both the original variant and XBB variants, the levels for XBB.1.5 were 4.6x lower and XBB.1.16 1.9x lower than the monovalent version. 11/

To keep the overall vaccine dose the same, the bivalent version has only half the amount of each variant so the immune system only gets exposed to half the amount as well. 12/

Most people now have either been vaccinated with one or more brands of the original vaccine formula or infected with the virus so would not be in a situation above where they are getting their first 2 doses of vaccine and no prior infection. 13/

What do vaccination responses look like with a new vaccine formula used as a booster dose for people with prior vaccination? 14/

The next part of Novavax's presentation seems like they are trying to game the system a little. They show results from vaccinating mice but with 2 bivalent (original variant + BA.5) doses which Novavax has never made available to the public and then adding a new XBB booster. 15/

In order for a human to get remotely close to this scenario they would need to have been infected by the BA.5 variant twice which would not induce the same immune response as the vaccine... 16/

... or be infected with BA.5 once and received an mRNA bivalent BA.5 vaccine so still not identical but at least would have exposed the immune system to a multiple looks at the mutations of BA.5. 17/

It is important to point out that research studies have found when people have been vaccinated with the original variant or infected with early variants of COVID-19 your immune system will favour generating antibodies for those variants people were originally exposed to. 18/

@yunlong_cao has done some great work related to this immune imprinting which you can read more about here ( ). 19/

https://twitter.com/yunlong_cao/status/1653804041821093889

@yunlong_cao found that bivalent vaccines which still contain the original strain are harming efficacy (which we also see above in Novavax's own results) and the original strain should be abandoned with updated vaccines. 20/

Importantly, he also found that you need at least 2 exposures to the newer Omicron variants in order to overcome this immune imprinting and start generating new antibodies to the updated variant ( ). 21/

https://twitter.com/yunlong_cao/status/1653805038320635906

That means the people who have been the most cautious and have avoided getting infected in the past 1.5 years may need two booster doses of the updated XBB vaccines to get their 2nd exposure for the immune system to generate new XBB specific antibodies. 22/

For the people who were infected more recently, one XBB vaccine booster would likely act as the second exposure. 23/

He also warns that even with multiple exposures, the neutralization levels for people exposed to early COVID variants/vaccines will not be as strong as people getting the updated XBB.1.5 based vaccine as their first exposure. 24/

Now that you are up to speed on potential issues with immune imprinting, Novavax using 2 doses of bivalent vaccine with BA.5 is giving the immune system of the mice two exposures to BA.5 allowing it to create BA.5 specific antibodies. 25/

Then when Novavax adds a XBB specific booster dose after 2 initial bivalent BA.5 doses, all Omicron based variants may get a more significant increase than if they just used 2 original vaccine doses + XBB booster. 26/

You can see the mice neutralization levels here:
8,413 = XBB.1.16 (2x Original&BA.5 + XBB.1.5 boost)
6,367 = XBB.1.5 (2x Original&BA.5 + XBB.1.16 boost)
5,816 = XBB.1.5 (2x Original&BA.5 + XBB.1.5 boost)

27/

4,778 = XBB.1.16 (2x Original&BA.5 + XBB.1.16 boost)
138 = XBB.1.16 (2x Original&BA.5)
123 = XBB.1.5 (2x Original&BA.5)

28/

Thankfully Novavax shows a scenario using 2x original variant vaccine doses (like people actually got) with rhesus macaques adding a boost of XBB.1.5 specific vaccine. 29/

Sure enough, while you do get a significant increase in neutralization against XBB.1.5 and XBB.1.16, you can see the response is much lower than using 2 doses of BA.5 vaccine first, or the bivalent (original+BA.5) first like they did in the mouse scenario above. 30/

rhesus macaques neutralization levels here:
8,734 = XBB.1.5 (2x BA.5 + XBB.1.5 boost)
6,317 = XBB.1.5 (2x Original&BA.5 + XBB.1.5 boost)
5,361 = XBB.1.16 (2x BA.5 + XBB.1.5 boost)

31/ Click "Show replies" 👇 to continue.

4,379 = XBB.1.16 (2x Original&BA.5 + XBB.1.5 boost)
1,376 = XBB.1.5 (2x Original + XBB.1.5 boost)
1,167 = XBB.1.16 (2x Original + XBB.1.5 boost)

32/

Novavax describes the differences in mutations between XBB.1.5, XBB.1.16 and XBB.2.3 as a way to justify recommending the use of XBB.1.5 for their updated vaccine formula. 33/

@CorneliusRoemer points out, a main differences in XBB.1.16 is 478R but this mutation is actually arising independently in sub lineages of all three of those variant families so XBB.1.16 is more likely to be closer to future variants than XBB.1.5 ( ). 34/

https://twitter.com/CorneliusRoemer/status/1669322887365292033

Another reason why Novavax may potentially be pushing XBB.1.5 as the variant of choice for boosters is that they started working on producing large quantities of XBB.1.5 based material for their vaccines. 35/

That means they could have XBB.1.5 booster doses commercially available soon while another choice like XBB.1.16 would take longer to bring to market. Novavax will also be using single dose vials for their XBB.1.5 vaccine. 36/

Novavax also introduced another method of measuring how well immune response stops COVID-19 from entering cells with their hACE2 receptor binding inhibition assay which they found correlated very well with neutralization levels. 37/

Looking at receptor inhibition in rhesus macaques, they found boosting with XBB.1.5 using various regimens produced comparable levels for XBB.1.5, XBB.1.16 and XBB.2.3. 38/

Novavax also looked at CD4+ T-cell responses and found Th1 and Th2 cytokine levels were similar for XBB.1.5 and XBB.1.16 irrespective of whether the mice had 2 doses of original vaccine and then XBB.1.5 booster or 2 doses of bivalent (original+BA.5) first. 39/

Questions about Novavax's presentation at the FDA meeting start here ( ). 40/youtube.com/live/gBOyPREXG…

A member asked about Novavax's CD8 T-cell response and Dr. Dubovsky responded that protein based vaccines like theirs are not expected to generate strong CD8 responses and while the Novavax vaccine does elicit a CD8 response, it is not as robust as other vaccine platforms. 41/

Novavax also mentioned that their timeframe to manufacture is similar to flu vaccines where they need approximately 6 months from the time a strain is chosen to commercial availability. 42/

Since they have also started the process to manufacture XBB.1.16 even before the FDA meeting, it could potentially be available about 8 weeks after XBB.1.5 was commercially available if XBB.1.16 was selected by the FDA. 43/

The process Novavax has been using is monitoring COVID-19 variants and developing candidates based on the ones they find most interesting. 44/

The candidates are then tested in animals to see how well they respond so Novavax is closer to commercial scale production should they need to produce a vaccine for a specific variant. 45/

There has been a ton of anecdotal evidence that Novavax vaccine doses seem to have less strong reactions compared to mRNA doses with people barely having sore arms and not feeling like they have been hit by a truck for a day or two. 46/

Now there is a preprint study (supported by Novavax) that compares the reactogenicity (frequency of side effects) of Novavax with mRNA vaccines ( ). H/T: @michaelzlin 47/ https://t.co/uOWyI8q64Dmedrxiv.org/content/10.110…

You can see my previous threads on Novavax to learn how it is different from mRNA vaccines and what some of the benefits of this vaccine platform are ( ). 48/

https://twitter.com/jeffgilchrist/status/1597228107919826946

A second Novavax thread on how the original Novavax vaccine formula compares to the latest BQ and XBB variants is here ( ). 49/

https://twitter.com/jeffgilchrist/status/1621843982857785344

You can find all the presentations from the FDA VRBPAC meetings including presentations from Pfzier and Moderna ( ). 50/fda.gov/advisory-commi…

On the mRNA front, it seems Moderna found better results using a bivalent BA.5+XBB.1.16 vaccine ( ). 51/

https://twitter.com/CorneliusRoemer/status/1669332919460978689

Pfizer on the other hand found a better response using a monovalent XBB.1.5 booster compared to a bivalent BA.5+XBB.1.5 booster ( ). 52/

https://twitter.com/CorneliusRoemer/status/1669337630054694919

The FDA released a statement after the meeting they are recommending a monovalent (just 1 strain) COVID fall vaccine booster based on the XBB variant lineage of Omicron with a preference for XBB.1.5 ( ). 53/fda.gov/vaccines-blood…

With flexibility given to vaccine manufacturers it will be interesting to see which formulas are actually available for the fall booster from each company and when. 54/

It will also be interesting to see what governments decide for who is eligible for fall boosters and how frequently. 55/

Will the regulatory bodies take into account that some people may need two doses before their immune systems start producing new antibodies to the XBB.1.5 vaccine or will they just assume everyone has already been infected multiple times already? 56/

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