Thread by @celinegounder

1/ Important new research by @KizzyPhD & other @NIAIDNews scientists on the Moderna vaccine in non-human primates.

They gave the primates 2 doses of the Moderna vaccine 4 weeks apart.

And challenged them with Delta variant virus 1 year later.

biorxiv.org/content/10.110…

2/
Gray: unvaccinated
Red: vaccinated

After vaccination, binding antibody levels:
- peaked at 6 weeks
- dropped weeks 6-25
- rate of decline slowed weeks 25-48

3/
Serum neutralizing antibody titers:
- dropped weeks 6-24
- rate of decline slowed weeks 24-48
- were highest vs D614G (early variant)⚫️>Gamma🟢>Beta🔴>Delta🔵

4/ This same pattern was observed with a pseudovirus assay:
- decline in neutralizing antibody titers over time
- lower neutralizing antibody titers against the Delta variant vs the early D614G variant

5/ See also:

6/ Over time, antibody avidity (i.e. the strength of binding to Spike protein) got better 6-24 weeks after vaccination.

This likely reflects somatic hypermutation & affinity maturation.

https://twitter.com/celinegounder/status/1417550246142529536?s=20

7/ They also looked at antibody titers in the lungs (bronchoalveolar lavage, BAL) & nose (nasal washes).

Binding antibody titers in the lungs dropped weeks 6-25, & then the rate of decline slowed.

8/ Among vaccinated primates challenged with Delta virus, antibody titers in the lungs⬆️ & peaked by day 4.

Among unvaccinated primates challenged with Delta virus, antibody titers in the lungs⬆️ days 4-14.

9/ Binding antibody titers in the👃🏾peaked later than in the🫁at 25 weeks & then remained stable out to week 42.

10/
Among vaccinated primates challenged with Delta virus, antibody titers in the👃🏾⬇️by day 4.

Among unvaccinated primates challenged with Delta virus, antibody titers in the👃🏾⬆️ by day 14.

Antibodies in the👃🏾may be cleared differently than in the 🫁.

11/ They also used a Spike protein-ACE2 binding inhibition assay to assess antibody function.

Binding in🫁 peaked at 6 weeks after vaccination & declined by 42 weeks.

12/ The Spike protein-ACE2 binding inhibition assay found that binding in👃🏾increased until week 25 & remained elevated at week 42 after vaccination.

13/ They assessed S protein-specific memory B-cells after vaccination with flow cytometry.

The % of S-protein specific memory B-cell responses peaked at 6 weeks after vaccination & then decreased by week 25.

14/ Over the course of a year, Spike protein-binding B-cells shifted from activated memory phenotype to activated/resting/tissue-like memory cells.

15/ Spike protein-specific T-cell responses were also assessed.

Th1 responses were detected at week 6 & ⬇️by week 25. They were low-undetectable by week 42.

16/ Tfh responses were detectable by week 6 & ⬇️by week 42.

17/ Th2 & CD8+ T-cell responses were low after vaccination.

18/ After Delta virus challenge, there was significantly less viral replication in 🫁 by day 4 among vaccinated vs unvaccinated primates.

19/ After Delta virus challenge, there was significantly less viral replication in👃🏾by day 2 among vaccinated vs unvaccinated primates, but the overall reduction in viral replication was less in👃🏾than in 🫁.

20/ Tissue culture infectious dose was also assessed from 🫁&👃🏾samples.

Viral replication in 🫁&👃🏾 of vaccinated primates was lower than for unvaccinated primates.

By day 4 after Delta virus challenge, replication in🫁was undetectable in almost all vaccinated primates.

21/ Viral replication in the 👃🏾of vaccinated primates was lower than for unvaccinated primates, but not zero.

22/ IN SUMMARY:

Unvaccinated and Moderna vaccinated primates were challenged with the Delta variant ~1 year after vaccination.

Four days after challenge, vaccinated primates had NO culturable virus in the lungs, but virus was culturable in the nose.

23/ Antibody-related protection in the lungs is durable but delayed.

It takes time for memory B-cells to rev up & make antibodies.

24/ Note that enough virus made it into the 🫁 of vaccinated primates to elicit a local anamnestic antibody response and a bump in Spike protein-specific B- & T-cell populations.

25/🫁from vaccinated & unvaccinated primates were examined 7 days after Delta virus challenge.

Viral antigen was detected in🫁of all unvaccinated primates & none of the vaccinated primates.

Inflammation was:
- minimal-moderate among vaccinated
- minimal-severe in unvaccinated

26/ Binding & neutralizing antibody titers declined over one year after vaccination leaving the lungs susceptible to viral infection & replication in the first couple days after challenge.

But the local anamnestic response was sufficient to prevent severe disease.

27/ Neutralizing antibodies are a good correlate of protection soon after vaccination.

A year after vaccination, memory B-cells may be a better correlate of protection.

28/ If the goal is to prevent infection in the👃🏾&🫁, it’s likely primates (& people) will need repeated (yearly?) vaccine boosters.

If the goal is to prevent severe disease, protection from the mRNA vaccines appears durable (at least out to 48 weeks).