Thread by @jeffgilchrist

Novavax JN.1 Vaccine Neutralization

Novavax revealed they had selected the original JN.1 variant as their fall booster and recently released neutralization results on non-human primates (Macaques) including a more recent KP.2 FLiRT variant. 🧵1/

Recall that the JN.1 variant became dominant in many parts of the world in December 2023 so by the time the fall 2024 vaccine program rolls out it will be almost a year old. 2/

Lets look more closely at the neutralization results that Novavax did provide in slide 14 of their investor presentation on May 10th ( ). 3/novavax.widen.net/s/gvwfqkhbhm/2…

The graph shows pseudovirus neutralization pre-boost on day 357 for JN.1 around 128 pVN50 and KP.2 at 181 pVN50. Then post-boost on Day 371 for JN.1 of around 5,132 pVN50 and KP.2 around 2,660 pVN50. 4/

There are several things that people need to understand about this graph and results. First, these are not results for humans but non-human primate Macaques so may be different in humans. 5/

Second, you need to look at the fine print at the bottom of the slide highlighted in yellow. There is a typo in the fine print and JB.1 should actually be JN.1. 6/

Also it is important to understand the vaccine history of these macaques and you can see they already had three (3) XBB.1.5 vaccine doses on day 1, 21, and 211 while most humans have only received one XBB.1.5 vaccine dose or possibly just getting their 2nd now. 7/

Also note the macaques had a JN.1 dose on day 246 so the "Pre Boost" results are actually what you get 3.7 months after just one (1) JN.1 dose and the "Post Boost" results are the neutralization levels after the second JN.1 vaccine dose. 8/

The wording they used in the slide titles are a little confusing. More accurately it should say, "Pre 2nd JN.1 Boost (D357)" and "Post 2nd JN.1 Boost (D371)". 9/

There was a 111 day (almost 4 month) time between the macaques getting their first JN.1 dose and them measuring neutralization levels for the first graph, and then 14 days (2 weeks) later measuring neutralization levels again after the second JN.1 dose. 10/

I have created my own graph to make it easier to see and understand the timeline of which vaccine doses and when. The third XBB.1.5 dose was after 6.3 months and the first JN.1 dose was only a month later, and the second JN.1 dose almost 4 months after the first JN.1. 11/

How do the neutralization levels in macaques compare to last year's XBB.1.5 booster and to the original COVID variant ( )? 12/nature.com/articles/s4159…

pVN50 Neutralization Levels

16,384 = Original Variant [2x original + 1x XBB.1.5]
5,132 = JN.1 [3x XBB.1.5 + 2x JN.1]
2,660 = KP.2 [3x XBB.1.5 + 2x JN.1]
1,448 = BA.5 [2x original + 1x XBB.1.5]

13/

1,448 = XBB.1.5 [2x original + 1x XBB.1.5]
182 = KP.2 [3x XBB.1.5 + 1x JN.1]
128 = JN.1 [3x XBB.1.5 + 1x JN.1]

14/

Neutralization levels are much lower with newer variants than the original variant and these macaques needed two JN.1 doses to get significantly higher neutralization than with just 1 dose. 15/

It would be much more helpful to see what the neutralization levels were using a combination of vaccines that the general population actually had access to like if they took last year's results of 2x original and 1x XBB.1.5 and then added 1x JN.1 vaccine dose. 16/

Even 3x original and 1x XBB.1.5 and 1x JN.1 vaccine are all reasonable combinations for people to have received. 17/

Our immune systems when exposed to newer variants seems to continue using the original (or first exposure) as a baseline and will create antibodies that cross-react with the original and the new variant (parts that are still common between the two). 18/

That means the new antibodies are not as good of a match as they would have been if they were designed solely for the new variant and neutralization levels are thus lower. 19/

You can read more about immune imprinting here ( ) and ( ) and ( ). 20/cell.com/immunity/fullt…
cell.com/immunity/abstr…
nature.com/articles/s4158…

It is also important to note that antibody neutralization is just one aspect of the immune system and does not provide the entire picture of how well someone will do when exposed to a virus. 21/

The WHO announced their recommendation for the fall 2024 COVID variant to be something in the JN.1 lineage with a special note about taking into account certain mutations like FLiRT which were rapidly increasing globally. 22/

Shortly after, the US VRBPAC meeting to choose a COVID variant for their fall booster program was postponed until June, many thinking this was to provide more time better understand the impact of these new mutations. 23/

It will be interesting to see if VRBPAC recommends something newer and more specific than JN.1 and if Novavax will be required to change the content of their fall 2024 vaccine. 24/

One of the variants that was not tested by Novavax is the even more immune evasive KP.3 variant which has an important Q493E mutation ( ). 25/

KP.3 is currently the most prevalent variant here in Canada and growing quickly in many other countries like Australia, Japan, New Zealand, Spain, and the UK. Visualization by @Mike_Honey_ 26/

There are also LP.1.* and JN.1.50 variants that are growing quickly that we should keep our eyes on. COVID has not stopped mutating and has been continually evolving to evade immunity generated by previous variants. 27/

It may be better to look at where the virus is going and not what it did almost a year ago. 28/

@threadreaderapp please unroll

Some people do not realize the original graph is in log scale so I created a linear one easier to see. The neutralization increase was actually 2.7x lower for KP.2 than JN.1 after the second JN.1 dose and the absolute neutralization of KP.2 was almost half that of JN.1. 29/

Correction that should be LB.1.* we should be keeping an eye on and not LP.1. 30/

Things are getting a bit more complicated. Novavax presented at the FDA VRBPAC meeting and still using ambiguous wording for their dose schedule but someone asked them directly what the dose schedule was ( ). 31/youtube.com/live/weaKQiFk_…

Dr. Walker stated it was 2 doses of XBB.1.5 a month apart, then 1 dose of XBB.1.5 at month 6 and 1 dose of JN.1 at month 11. So it may be that you don't need two doses of JN.1 to get those post-boost neutralization levels. 32/

That means there were two typos in the investor slides which said JB.1 (which I confirmed they meant JN.1) but also day 246 would have to be wrong as well if the JN.1 boost was actually at 11 months. It would be much easier if there as a pre-print showing all the details. 33/