Delaying a COVID vaccine’s second dose boosts immune response

[Evo]

TL;DR Summary

Older people who waited 11–12 weeks for their second jab had higher peak antibody levels than did those who waited only 3 weeks.

I was wondering if @Ygggdrasil has more information on this. Is there only documentation on people over 80? What is the likely hood that this would also be the case for those younger? I believe the study is only for the Pfizer vaccine.

Older people who waited 11–12 weeks for their second jab had higher peak antibody levels than did those who waited only 3 weeks.

Now, a study suggests that delaying the second dose of the Pfizer–BioNTech mRNA vaccine could boost antibody responses after the second inoculation more than threefold in those older than 80.

Peak antibody levels were 3.5 times higher in those who waited 12 weeks for their booster shot than were those in people who waited only 3 weeks. Peak T-cell response was lower in those with the extended interval. But this did not cause antibody levels to decline more quickly over the nine weeks after the booster shot.

https://www.nature.com/articles/d41586-021-01299-y

Is the amount of gain worth the wait?

I was ill since the Pfizer vaccine came out (the one I wanted), so just recently got my first dose. My doctor also believes I had Covid in March of last year, plus I rarely go out, doing all of my shopping online, even my meds are delivered.

I have the 2nd dose due next week, but although I'm not near 80, I'm considered a senior citizen, I'm wondering if I should consider waiting a few more weeks for my second dose. No Yggg, not asking your advice on this, just wondering out loud.

 

[jim mcnamara]

https://asv.org/vaccine-townhall/
Go to this site, register for a zoom meeting with senior virologists and immunologists.

They know the answers... if there are any.

 

[atyy]

In the UK, it has been decided that the gain is not worth the wait because of the delta variant.

Originally, the UK used longer periods (up to 12 weeks) between doses, because they reasoned that with doses limited, it would be better to give good protection to many, rather than excellent protection to a few. They were criticized, for not following the interval between doses that had been trialled, but the trial data for some vaccines had shown that one dose already gives reasonable protection (eg. ~80% for the Pfizer vaccine), and experience with other vaccines had shown that it was more important to have a minimum (not so much a maximum). The study referenced by the article in the OP supports the UK's original decision.

However, with the delta variant, symptomatic protection on the first dose is only about 33% for AstraZenca and Pfizer vaccines. For the Pfizer vaccine, 2 doses still confers about 88% protection against symptomatic infection. So the second dose is important. Because of the new data regarding the delta variant, the UK has brought forward second doses from 12 to 8 weeks, at least for people in vulnerable groups.
https://www.pulsetoday.co.uk/news/c...s-expanded-to-40-49s-to-combat-delta-variant/
https://www.itv.com/news/wales/2021...elta-variant-continues-to-spread-across-wales

 

[Evo]

In the UK, it has been decided that the gain is not worth the wait because of the delta variant.

Originally, the UK used longer periods (up to 12 weeks) between doses, because they reasoned that with doses limited, it would be better to give good protection to many, rather than excellent protection to a few. They were criticized, for not following the interval between doses that had been trialled, but the trial data for some vaccines had shown that one dose already gives reasonable protection (eg. ~80% for the Pfizer vaccine), and experience with other vaccines had shown that it was more important to have a minimum (not so much a maximum). The study referenced by the article in the OP supports the UK's original decision.

However, with the delta variant, symptomatic protection on the first dose is only about 33% for AstraZenca and Pfizer vaccines. For the Pfizer vaccine, 2 doses still confers about 88% protection against symptomatic infection. So the second dose is important. Because of the new data regarding the delta variant, the UK has brought forward second doses from 12 to 8 weeks, at least for people in vulnerable groups.
https://www.pulsetoday.co.uk/news/c...s-expanded-to-40-49s-to-combat-delta-variant/
https://www.itv.com/news/wales/2021...elta-variant-continues-to-spread-across-wales

Wow, Thank you @atyy ! I will be keeping my appointment next week even though I might not be at high risk. You never know, I've had Rocky Mountain Spotted Fever, an EXTREME case of Mononucleosis where I was unconscious in the hospital for several days, just too many weird things to mention, including Covid last year. I am supposed to go to Scotland in a couple of months, but now I am wondering if they are going to tighten things up again with the Delta variant. They JUST opened up travel from the US! They had required a 10 day quarantine at a government hotel of their choice at YOUR expense PRIOR to the start of your vacation! Say what?

 

[atyy]

Oh my, the fever and mononucleosis sounds terrible - hope you are mostly now?

 

[Evo]

Oh my, the fever and mononucleosis sounds terrible - hope you are mostly now?

I was better then than now, mostly. But not unconscious. Well, some days I wish I was unconscious.

 

[Tom.G]

Just as a heads-up:
Having had Mononucleosis (many years ago), I discovered it has a long tail of the 'Feel Bads.' So you may discover that a long overseas trip is not as rewarding as hoped.

Anyhow, Best Wishes and I hope you are feeling better soon.

Cheers,
Tom

 

[Evo]

Just as a heads-up:
Having had Mononucleosis (many years ago), I discovered it has a long tail of the 'Feel Bads.' So you may discover that a long overseas trip is not as rewarding as hoped.

Anyhow, Best Wishes and I hope you are feeling better soon.

Cheers,
Tom

Thanks Tom, but I was only 14 when I had mono, maybe before you were born.

 

[Vanadium 50]

You should follow the breadcrumbs to the original paper.:

(1) As you said, this study was done on people 80 and up, with mean ages in the mid-80's. This is reasonable when trying to draw conclusions about the people Covid actually kills. It is not directly relevant to the population at large.

(2) There are 55 data points in the relevant category. There is a substantial overlap in the response of people who got done 2 early and who got it late. The effect is driven by a small number of people.

(3) If you believe that the vaccine is 95% effective, the right question is how much more effective is a delayed second dose? If I look at the 79 people who were on the regular schedule, I expect 4 people to still be susceptible. If I look at how many in the delayed group are at that point or below, it's 2. But 53 out of 55 is 96%. That's what we are talking about -95% vs. 96%.

(4) The exact same study could have been cast as "Older people who were tested 2 weeks after their second jab had higher higher peak antibody levels than did those who waited 10-11 weeks to be tested."

 

[Fra]

The study referenced by the article in the OP supports the UK's original decision.

I'm in Sweden, and on the pfizer vaccine, the manufacturer prescribes minimum 3 weeks between 1st and second dose. Here the recommendation is now extended to 7 week. But it's obvious that the reason is like that in UK. A possible interpretation of some studies that there are other reasons to wait seems too politically convenient for decisions makers.

Set aside the political agenda, I am not sure I follow the conclusion. Even early on in the pandemi, if I remember correctly (dont remember the reference) was speculated that people wither a more efficient T-cell response to Covid-19 - had a lower production of antibodies? That makes sense from the point of regulatory economy of the immune system. So how come the the conclusion that a higher peak antibody production at some point, means a better total immunity in long term? Is this a guess or is it some "virology-theorem" that higher antibody response correlates to long term immunity?

Especially as it was noted that the T-cells activity was lower? Isnt it a possibility that the peak antibody response was higher - BECAUSE the T-cell reseponse was less prompt? And how we know which is more important long term?

Can anyone with knowledge on immunology explain? Here the argument that "wait longer is good" is at least in the public used in a generic not convincing way to make people accept the extra wait?

/Fredrik

 

[Ygggdrasil]

A few thoughts (since I was tagged in the OP):
1) This issue was brought up in a previous thread from a month ago linking to the same news piece: https://www.physicsforums.com/threa...econd-dose-pfizer-vaccine-in-elderly.1003245/

2) As I stated in that thread, the Pfizer vaccine already has a very high efficacy (~ 95%), so there's not a lot to gain from delaying the dose. The information, however, could be relevant to designing future mRNA vaccines, however.

3) We're not completely sure about the correlates of protection for COVID-19 (i.e. what measurable values correlate well with protection against infection). That is to say, it's not exactly clear whether higher antibody levels would necessarily mean stronger protection. Given the already high efficacy of the 3 week dosing schedule, it's likely that the lower level of antibodies from the 3 week dosing schedule is already sufficient for protection and levels above that aren't really that useful.

3) As mentioned by @atyy, based on data from Public Health England, there is a potential danger in extending the period between the 1st and 2nd dose given that people are still vulnerable to infection during that period, especially to some of the newer variants (delta in particular).

4) There is some data from the AstraZeneca vaccine suggesting that a longer interval between doses is beneficial. However, a) the data is fairly preliminary and not that definitive yet, and b) the underlying reason for the effectiveness of a longer interval is probably different for the AZ vaccine (a viral vector vaccine) and the mRNA vaccines. Essentially, the AZ vaccine is itself a virus that is subject to attack by the immune system. Having a longer delay between doses of the AZ vaccine could provide greater protection because it might provide a weaker immune response against the second dose, which would improve the effectiveness of the second dose at generating spike proteins for the immune system to recognize (see further discussion here).

 

[atyy]

A possible interpretation of some studies that there are other reasons to wait seems too politically convenient for decisions makers.

One can just read the studies as saying it's not worse to wait, which I think is all that the decision makers hoped for. The reasons to wait are supported by our general understanding from understanding that for other vaccines, there is a minimum period between boosters, but less often a maximum period.

Even early on in the pandemi, if I remember correctly (dont remember the reference) was speculated that people wither a more efficient T-cell response to Covid-19 - had a lower production of antibodies?

I haven't seen this? I think it's more that antibodies are not the only indication of protection against severe disease. One could have low antibodies (especially over time), but the memory T-cells could still provide good protection.

https://science.sciencemag.org/content/371/6529/eabf4063
Immunological memory to SARS-CoV-2 assessed for up to 8 months after infection
"Whereas sterilizing immunity against viruses can only be accomplished by high-titer neutralizing antibodies, successful protection against clinical disease or death can be accomplished by several other immune memory scenarios. Possible mechanisms of immunological protection can vary according to the relative kinetics of the immune memory responses and infection. For example, clinical hepatitis after hepatitis B virus (HBV) infection is prevented by vaccine-elicited immune memory even in the absence of circulating antibodies, because of the relatively slow course of HBV disease (32, 33). The relatively slow course of severe COVID-19 in humans [median 19 days post–symptom onset (PSO) for fatal cases (34]) suggests that protective immunity against symptomatic or severe secondary COVID-19 may involve memory compartments such as circulating memory T cells and memory B cells (which can take several days to reactivate and generate recall T cell responses and/or anamnestic antibody responses) (19, 21, 31)."

 

[Fra]

I haven't seen this? I think it's more that antibodies are not the only indication of protection against severe disease. One could have low antibodies (especially over time), but the memory T-cells could still provide good protection.

I can't find wherever I got this from, but in any case I think you are right that it somehow relates to the T-cell vs B-cell function, the issues are related.

What are the roles of antibodies versus a durable, high quality T-cell response in protective immunity against SARS-CoV-2?
"Antibody response is often a poor marker of prior Coronavirus infection, particularly in mild infections, and is shorter-lived than virus-reactive T-cells; strong antibody response correlates with more severe clinical disease while T-cell response is correlated with less severe disease; and antibody-dependent enhancement of pathology and clinical severity has been described. Indeed, it is unclear whether antibody production is protective or pathogenic in Coronavirus infections. Early data with SARS-CoV-2 support these findings
"
-- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7452821/

My main abstract physics interest in the cellular life is to understand the possible regulatory objectives from evolutionary perspective (thw why), in constrast to the detailed chemistry (how). Even from qbist perspective, trying how a cells is making rational decisions is interesting. This is my sick reason for butting into this. I am fascinated by how abstractions in complex and the simple are sometimes the same. Immune response from a resource allocation perspective
"The costs of using the humoral component (B-cells and type two T-helper cells) are thought to be small compared with those of innate and cell-mediated defenses because the humoral immunity is associated with the production of anti-inflammatory cytokines; however, lymphocyte proliferation and diversification during the developmental period require substantial energy and nutrients (Lee, 2006). "
-- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3571735/

Are there any knowledge on B-cell vs T-cell systems, from the perspective of regulatory economy both at present and it's evolutionary origins?

While the T-cell are "expensive" and slow to rig (taking weeks etc?), I understand them as a last line of defence, but if that is solid enough and in place, and sufficient to stop the infection to spread, perhaps it costs less than B-cell activation, and lead to a smaller Ab-peak? But if the T-cell defence is less effective, perhaps the Ab release is upregulated leading to a stronger peak? Or can one say this is just wrong?

What can we infer from that the Ab-peak is 3.5 times higher, and the T-cell response 3.5 lower?
Is the Ab-peak upregulated, because the T-cell response is not judged by the immune systems as sufficient (as the immune system also should not overreact)? Or was the B-cells more ready for a quick Ab release in the delayed second dose? Any other options?

Anyway, when i took my first dose recently the nurse told me confidently, that "I will get a better immunity in long term, if I wait longer". And just like the typica sales guy would say when you are to buy something "I have one of these myself!", the nurse told me to add the emphasis "I personally waited 12 weeks for my second shot!"... so they are making us feel like stupid customers. No thanks for the sales talk.

But I have a feeling it's something they are instructed to say to encourage us to wait. (The booking system here, formally ALLOWS me here to book the second shot earlier if I am bold, it's not strictly controlled as it seems, it's up to the patient to wait before booking second shot).

/Fredrik