JCVI extension of vax dosing interval to 12 weeks is a great public health decision.

3.5X higher peak antibody levels w/ Pfizer if delayed boost vs 3 week.

Really important for protection against variants and duration esp in vulnerable🧵


We kept seeing 1 dose vax after prior infxn boosting Ab tires 3X higher than 2 doses at the standard 3 week interval. Some of us wondered if this was from optimised prime-boost interval at the time...

It now looks like a probable explanation.


3 weeks on short side of intervals, where immune response hasn't completely matured after prime stimulus.

Delay may selectively expand population of long lived plasma cells (B cell derivatives) too.

Delayed boost shown to have better Ab response across prev vax types👇

This is particularly important in the vulnerable elderly population where immune response is slower with later detectable seroconversion, and lower final Ab level too.

When it comes to variants the way we measure 'immune evasion' typically in labs (in vitro) is what concentration or dilution of blood serum containing Ab is needed to neutralise the virus to prevent growth on plates. (usually 50% of baseline viral plaque growth)

For Pfizer serum after 3 week dose interval compared to wild type SAR-COV-2 virus it takes approximately 3X higher serum concentration to achieve viral neutralisation for UK B1.1.7 and Brazilian P.1 and 8X higher serum concentration for South African B1.351.

This happens bc mutations in viral spike protein alter its amino acid residues and the protein shape our antibodies recognise and form hydrogen bonds with.

The mutations lower affinity (or binding association constant) between our generated antibodies and the spike protein.

Spike mutations thus affect antibody binding equilibrium constant (Keq), the reaction of antigen (Ag) and antibody (Ab) binding to form antigen-antibody complex (Ab-Ag).

Shifting equilibrium to the left (unbound)

(Ka/Kd= Ka =Keq, where Kd is the dissociation constant)

Since Ab bind less strongly to mutant spike antigen the virus is no longer trapped and free to infect cells and replicate.

But simply by increasing concentration of serum Ab we can mitigate this and shift antibody binding equilibrium back to where it was pre-mutation.

Whilst not exactly linear nor necessarily at equilibrium in dynamic human system, serum w/ 3.5X higher Ab level should neutralise variants B1.1.7, P.1 and even Indian B1.617.2 similarly as serum from someone w/ 3 week Pfizer interval neutralising wild type virus.

In addition to providing likely better effectiveness against variants in the short term, delayed dosing will also increase durability of protection.

Ab levels decay w/ time and starting from a higher initial peak helps.

But decay rate itself is proportional to peak level!

This is seen both in Ab longevity studies from natural SARS-COV-2 infection and also after vaccination of other viruses. Where higher initial Ab titres lower the rate of Ab decay.

So duration of protection is even longer than expected from using a static decay model.

In summary JCVI delayed 12 dose:

⬆️ Ab level, particularly valuable in vulnerable elderly

- will effectively neutralize variants as well as WT (except B1.351) if compared to 3 week interval

- longer protection at high level (area under Ab curve)

- maximised vax resources

Puts UK in a strong position to deal with emerging variants in the coming months/years. More leeway for amount of 'immune escape' and time if boosters needed etc.

Canada following suit with 16 week interval now.

NB. Delayed boost increases Ab tires/VE for Oxford/AZ too👇

If accelerating dose interval <<12 weeks there should be real pressing need/risk of immediate infection...

2 doses definitely provides better protection against infxn, hospitalisation and death v 1 dose at any interval, but shorter interval will forgo longer term benefits.


• • •

Missing some Tweet in this thread? You can try to force a refresh

Keep Current with Devan Sinha

Devan Sinha Profile picture

Stay in touch and get notified when new unrolls are available from this author!

Read all threads

This Thread may be Removed Anytime!


Twitter may remove this content at anytime! Save it as PDF for later use!

Try unrolling a thread yourself!

how to unroll video
  1. Follow @ThreadReaderApp to mention us!

  2. From a Twitter thread mention us with a keyword "unroll"
@threadreaderapp unroll

Practice here first or read more on our help page!

More from @DevanSinha

29 Apr
Fantasy commentary letter in Lancet (not a peer reviewed study)!

It's an unreasonable proposition for most countries like the UK to achieve elimination + constraints of reality negates claimed economic and liberty benefits if attempted...


Despite pre-flight screening and quarantine Australia and New Zealand have failure rate of 4.8 per 100k travellers. SARS-COV-2 cases slip through!


Those cases slipping through results in necessary lockdown (regional or state wise) to eliminate community transmission.

Up to January 31, 2021:
Australia 7 failures, with 1 causing 800 deaths
New Zealand 9 failures, 1 causing an outbreak of 3 deaths

more since

Read 18 tweets
28 Apr
PHE study on household transmission after vax:

40-50% reduction if break through infxn

From contact tracing of 4.1k households where index vaxxed >21days and contact positive 2-14 days of index

4 Jan 4 - 28 Feb from 365k households w/ single index case and 1m+ contacts

1/ Image
No statistical difference between Ox/AZ and Pfizer efficacy for onward transmission

No statistical difference in effect by age

Well controlled:
adjusted for age of index case and contact, sex, region, calendar week, index of multiple deprivation quintile, household type


Pillar 2 symptomatic case only so may miss asymptomatic cases (=overestimate efficacy).
Assumed contact symptom >2days of index was transmission but cd be co-primary (=underestimate),
and all 2-14 days are household transmission not independent (=underestimate)

Read 4 tweets
30 Mar
Updated meta-analysis B117 mortality w/ new PHE sequenced Pillar1/2 study Oct-Dec

Major limit= underpowered
Only 36/2.8k deaths B117 cohort v 40 non-VOC
HR 0.9 [0.57,1.41]

(W/ updated LSHTM and Exeter papers, but now excl hospitalised HR studies)

🔺c40% mortality risk

Study still found B117 increased hospitalisation risk
HR 1.34 [1.07,1.66]

Unless in hospital mortality is lower in B117 (no clear difference) then over all fatality rate will necessarily be higher

A few other considerations 👇


From pathophysiology understandable why B117 might have higher morbidity/mortality.

Higher binding affinity to ACE receptor means more tissues or systems w/ lower expression may be affected

More replication (⬆️viral load) means more tissue damage and systemic inflammation

Read 4 tweets
15 Mar
COVID on the brain 🧠

Stroke like brain injury can be a life altering complication of SARS-COV-2 infection

Let's see how often is happens, what it looks like, and why.

A retrospective study was done in my own hospital trust :)

3,403 PCR+ COVID inpatients between March and May 2020

167 had neurological symptoms warranting neuroimaging

38 revealed vascular (ischemic or haemorrhagic) abnormality = 1.12% of total C19 inpatients

Mean age 59.7

Onset of neuro symptoms mean 10.1 days from admission

Even w/out COVID, many patients admitted for other reasons have strokes. However, in this COVID patient cohort when age adjusted the rate is ~5x ⬆️

87 vs 16 per 1000 hospitalised inpatients annualised rate

Read 10 tweets
5 Mar
Temperature and SARS-COV-2 transmission:

Some seasonality expected for resp viruses, hard to say how much. England had unique circumstance Feb 7-13th.

- week long cold snap across country of similar magnitude
- no change in restrictions
- no increase in daily mobility

Due to variables being reasonably controlled we can estimate how temperature may affect general transmission dynamics.

Note Seasonality: viruses transmit at ALL times of year but climate affects biology and behaviour which impacts on how much transmission occurs.

Cases by specimen date in England showed a marked deceleration in the rate of decline the week after the cold period. From more than -5% per day to less than -2%.

(daily change adjusted for day of the week effect in testing)

Read 14 tweets
22 Feb
1st dose hospitalisation vax efficacy

94% Oxford/Astra
85% Pfizer

Appears taken as point estimates for week 5 (28-34 days) post vax.

Pfizer data doesn't improve (declines even), but not too worrying yet... ImageImage
Scotland where data from care home residents and 85+ were vaxxed 1st. Follow up time after 5 weeks means age will confound VE. With few absolute events adjustment for age becomes statistically underpowered (and doesn't capture full care home risk). Hence wide confidence interval Image
Also interesting to think about vax tech.

Oxford uses chimp adenovirus vector. Although engineered not to replicate, it's tough and can persist for weeks-months before cleared. Continuing to stimulate immune response by causing Sars-Cov2 spike protein production. ImageImageImage
Read 5 tweets

Did Thread Reader help you today?

Support us! We are indie developers!

This site is made by just two indie developers on a laptop doing marketing, support and development! Read more about the story.

Become a Premium Member ($3/month or $30/year) and get exclusive features!

Become Premium

Too expensive? Make a small donation by buying us coffee ($5) or help with server cost ($10)

Donate via Paypal Become our Patreon

Thank you for your support!

Follow Us on Twitter!