Thread by @michaelzlin

Flew in from Asia today to learn the exciting news that Novavax's JN.1 booster has been approved!

So happy that the delay relative to RNA vaccines is less than a week. People will finally have a choice of RNA vs protein vaccines this fall.

What are the differences?

https://twitter.com/Novavax/status/1829612945338482755

I made this graphic to show how different vaccine types work (back in 2021).

We can just look at line 1 (protein vax like Novavax) and line 3 (RNA vax).

In protein vax, antigen-presenting cells take up the antigen to activate B cells and Thelper cells....

In RNA vax, your muscles cells take up RNA and translate it into antigen. This process tends to be a bit inflammatory (apparently that's inherent to RNA uptake) so some cells die and release proteins that are also taken up by antigen-presenting cells.

The main differences between protein and RNA vax in practice are threefold:

1. Cellular immunity, meaning CD8 cytotoxic T cell responses: RNA vax elicit this, whereas Novavax CTL responses are minimal.

RNA vax probably do so because having foreign antigens in muscle cells looks like a virus has infected those cells. The antigens are presented on MHC-I (whereas proteins ingested by antigen-presenting cells are expressed on MHC-II), and this is necessary for activating CD8 CTLs.

Cellular immunity provides a backup and mopping-up function after antibodies have cleared away viruses (note I did not use the term neutralize; more on why later), and lack of cellular immunity may cause prolonged disease. But cellular immunity is long-lived and broad-spectrum...

If you've had a RNA vax or a SARSCoV2 infection within the last 3 years, then you have cellular immunity. It's broad-spectrum as CTLs recognize many conserved regions of the spike (if you've only been vaccinated and never infected) or other viral proteins if you were infected.

And if you've never had a CTL response (because you only took Novavax vaccines and were never infected — a vanishingly small possibility), then if you get infected you will develop a CTL response in week 1 while antibodies are clearing the virus, after which CTLs help "mop up"

As you can see, I don't think much about keeping CTLs up. Once you have a CTL response (from RNA vax or infection), it stays with you. If you don't have one, you'll develop it during illness. It doesn't help prevent infection and having it ahead of time makes little difference.

The second difference between protein vax and RNA vax is the peak amplitude of antibodies. Peak antibody levels are higher with RNA vax. This is certainly an advantage of RNA, but it only lasts for 2-6 weeks after inoculation. Titers drop dramatically after that.

This wave is going strong, and does not look like it will peak within 6 weeks. There's a lot of disease going on now, as there was a month ago. It seems likely there will be virus going around at Halloween and Thanksgiving gatherings, and Christmastime-New Year parties too.

Data on superiority of RNA-boosted Abs in month 1:

As waves tend to last 3 months (and this one appears might even become 6 months), a 6-week period of somewhat higher protection doesn't seem so useful as how well a vax works over the entire wave, IMO.ncbi.nlm.nih.gov/pmc/articles/P…

And the data do show that in the long-term (measured from 3mo post-vax) Novavax is as good as RNA. Here's one study: sciencedirect.com/science/articl…

Now if there were no price to pay for having one month of high antibodies, then sure, why not RNA. But that brings us to difference #3 between protein and RNA vaccines: the RNA vax are stronger in their adverse effects on the immune system than any other vaccine we've ever taken.

IgG is the major class of antibodies your B cells make. When they encounter the same antigen repeatedly, often seen in autoimmunity or with parasitic infections, the IgG genes undergo "isotype switching" to IgG4, which lacks any of the "Fc effector" functions of other IgG types.

The Fc functions include antibody-mediated recruitment of phagocytic cells to engulf and destroy antibody-coated viral particles. We hear a lot about neutralizing antibodies because it's easy to test how well your blood neutralizes SARSCoV2 from entering cells, but in the body…

It's more efficient for an antibody to tag a virion, get the virion engulfed and destroyed, and for the antibody to be recycled to repeat the process. If neutralization were the only thing, we'd need more antibody molecules than spike proteins across all virions, a tall order.

An issue that's now well known is that RNA vaccines cause isotype switching to IgG4, which lacks these Fc functions. This was not the case with earlier vaccines, so appears to be the result of the strong B cell stimulation performed by RNA vaccines.
science.org/doi/10.1126/sc…

Novavax, likely because its stimulation method is slow and steady, instead of creating a hot and heavy pseudoinfection in your muscles like RNA, does not induce the IgG4 isotype switch. It instead generates more IgG3, with the most Fc effector function.
journalofinfection.com/article/S0163-…

So those are the 3 differences between Novavax and RNA: (1) CTL responses with RNA, (2) higher peak Abs with RNA, (3) faster conversion to non-catalytic IgG4 with RNA.

Actually there's a fourth: Side effects are stronger with RNA than Novavax.

Essentially the headache and fatigue we get from RNA vaccines is quite a bit out of line compared with historical flu vaccines, whereas Novavax is more in line with flu vaccines (not surprisingly, as both use proteins).

Here's one study; there are others:
mdpi.com/2076-393X/12/7…

So for those of use who have been following the development of RNA vaccines and watching the Novavax tortoise moving toward the finish line, the major difference has always been clear: RNA vax provide a strong stimulus, stronger than what we are used to in annual vaccines.

Without a doubt, for the initial rounds of vaccination in 2020 and 2021, RNA was a lifesaver. The higher reactogenecity was a small price to pay to avoid hospitalization. Issues with vaccine purity delayed Novavax, so we were lucky to have RNA ready.

However, now that we are getting into these 3- to 6-month long waves, now that nearly everyone has had COVID-19 and therefore has hybrid humoral and cellular immunity, we can rethink which kind of vaccine is appropriate on an annual basis.

Essentially now we are fighting off a chronic threat of COVID19. Vaccines are really not effective enough to be the only preventive measure. We'd have to get vaxxed 4 times a year, which is not going to happen. Instead we have to figure out our own behavioral risk/reward ratios.

For preventing transmission, the situation is similar to flu (a poor analogy as SARSCoV2 outcomes can often be more severe than flu). Perhaps the best we can do is avoid spending too much time in loud crowded indoor setting, and encourage people to test at the first symptoms.

So the vaccines now become a personal choice, and there is no right or wrong answer. But given the differences presented above, my own plan is to get 2 years Novavax (slow and steady baseline) and 1 year Pfizer-BioNTech (for a little CD8 T cell push).

If in a given year, we have a tightly timed surge for just 2 month (say Dec-Jan), then RNA may be worth considering, but that doesn't seem to be happening this year. So might was well do the lesser insult of protein, riding with the tortoise instead of the hare.

That's just me. Not medical advice. YMMV. This is essentially a willingness to take on slightly higher integrated risk of infection for a more balanced immune system.

Forgot to mention, there's a formulation difference between the JN.1 Novavax and the KP.2 Pfizer and Moderna. At the VRBPAC meeting, Novavax made a point that JN.1 was the father to all circulating strains and the antigenic differences were minor compared to the leap from XBB.

This sounded reasonable to me at the time, because in protein evolution we always evolve on the latest two generations in case the latest one becomes an evolutionary dead-end. The VRBPAC agreed with Novavax, which was why their recommendation was anything in JN.1.

Everyone thought that was settled, except the next day, FDA (withouth asking VRBPAC) announced they would prefer KP.2 which was the rising sublineage at the time. Pfizer and Moderna (who had presented results of KP.2 boosters to VRBPAC) immediately said they'd do it.

Hmm, I wonder who might have called their contacts at FDA?

But now KP.3 is the one going around. And Novavax's data are that their JN.1 vax neutralizes KP.3 well.

Even Moderna shows JN.1-to-KP.3 is better than KP.2-to-KP.3.

So Novavax was right.

https://x.com/JUurinmaki/status/1825034073690997055

BTW here's the adverse effect (AE) difference between RNA COVID-19 vax and seasonal influenza vax (SIV), which are protein vax.

RNA vax has ~2x higher rates of adverse effects than flu vax. And earlier we saw RNA vax has 2x higher AEs than Novavax.
jamanetwork.com/journals/jaman…

I've read it asserted in the literature that RNA vax reactogenicity is similar to seasonal flu vax; this is simply not true. Novavax and seasonal flu vax, however, are similar in reactogenicity, as expected as they are similar in mechanism.

BTW the paper above concluded adding flu to RNA vax doesn't increase reactogenicity, basically assuming readers are taking the RNA vax anyway. But the more interesting comparison is how RNA vax and flu vax compare. The paper never discusses the unfavorable result.

@JC99WHIT See science.org/doi/10.1126/sc…

And here's a thread on RNA-induced IgG4, by the scientist who discovered it. He said harms are unknown, which is still the case, but he believed we didn't have to worry as he couldn't see a need for annual RNA boosters! Maybe reasonable to be cautious.

https://x.com/kischober/status/1606366034654527523

Also Moderna causes more IgG4 switching than Pfizer-BioNTech, as expected for its larger dose of RNA, eliciting of higher Ab levels, and stronger side effects. So everything correlates.

https://x.com/kischober/status/1613630273228529665