Does increasing the gap between two Pfizer shots to 12 weeks provide higher levels of protection?

Question

When COVID-19 vaccines started rolling out, the UK prioritized administering the first dose to as many at-risk people as possible. As a result, the interval between the two doses was increased to up to 12 weeks.

Subsequently, there's been data that suggests this increases antibody responses in older people and, as recently as this week a UK government scientific advisor claimed "[t]here is a sort of sweet spot from about eight weeks onwards".

However, this is against WHO's recommendation:

A protective effect starts to develop 12 days after the first dose, but full protection requires two doses which WHO recommends be administered with a 21 to 28-day interval.

The CDC similarly recommends a gap of 3 weeks and notes that the "second dose may be given up to 6 weeks after the first dose", making no mention of the 8 week "sweet spot".

I understand UK's decision to delay is in the interest of public health, but is there any evidence that leans towards either 3 or 8 weeks gap as providing better protection than the other to an individual?

Answer 1

Is there any evidence that leans towards either 3 or 8 weeks gap as providing better protection than the other to an individual?

Providing a second dose earlier is recommended for the individual so that they will experience "full" protection earlier rather than later. As the WHO has noted, spreading out the second dose "enhances peak antibody generation in older people," which suggests "extend[ing] inter-dose intervals will result in a good immune response, even in older adults." I could not find data on vaccine efficacy for the Pfizer vaccine after extending dose intervals. For the AstraZeneca vaccine, extending the dose interval does increase the vaccine efficacy (from 56% for an interval of 4-8 weeks to 78% for an interval of more than 12 weeks).

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The WHO updated their interim recommendations on June 16, 2021. In the updated recommendations, they include a section on deferring the second dose. Here is the relevant part of that section:

WHO acknowledges that a number of countries face exceptional circumstances of vaccine supply constraints combined with a highdisease burden. Some countries have therefore considered delaying the administration of the second dose to allow for a higher initial coverage with one dose. This is based on the observation that efficacy has been shown to start from day 12 after the first dose and reached about 89% between days 14 and 21, at the time when the second dose was given. No data on longer term efficacy for a single dose of BNT162b2 currently exist from Phase 3 trials, as the trial participants received 2 doses with an interval between doses in the trial ranging from 19 to 42 days. Neutralizing antibody responses were shown to be modest after the first dose and increase substantially after the second dose, and the second dose increased the efficacy against symptomatic disease to 95%. Post second dose studies showed that immunogenicity in terms of neutralizing antibodies is increased with a longer inter-dose interval to 12 weeks (10) highlighting that extended inter-dose intervals will result in a good immune response, even in older adults.

Some countries have chosen an inter-dose interval of 12 weeks. Based on post-introduction vaccine effectiveness studies from these countries, data on persistence of post dose 1 effectiveness are currently available up to 10 weeks in the context of the ancestral virus and the variant of concern Alpha (B 1.1.7) (11). Evidence on the impact of variants of concern other than Alpha (B1.1.7) on first and second dose vaccine effectiveness is only just emerging. Effectiveness after a single dose of vaccine against COVID-19 associated with Delta (B 1.617.2) was lower than that against Alpha (B.1.1.7), whilst two dose effectiveness was similar for these two variants (12). These data highlight the importance of providing a second dose of vaccine in the context of circulating variants of concern that may lower the effectiveness of a single dose.

From reading the full report, the WHO's concern is not that efficacy will be worse when spreading apart the doses (once the second dose has been given), but that people with only one dose are more vulnerable before the time they receive their second dose.

The WHO does conclude that:

In conclusion, for countries that have not yet achieved high vaccine coverage rates in the high-priority groups who are experiencing a high incidence of COVID-19 cases combined with vaccine supply constraints, WHO recommends that such countries should focus on achieving a high first dose coverage in the high priority groups by extending the inter-dose interval up to 12 weeks.

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Bonus for those who read all the way here.

The UK has notably also administered the Oxford/AstraZeneca vaccine. For this vaccine, the WHO writes:

Exploratory analyses were conducted of vaccine efficacy 15 days or more after the second dose, according to the interval between the first and second doses. For about 59% of participants the interval was 4–8 weeks, for 22% 9–12 weeks and for 16% more than 12 weeks. The estimates of VE increased significantly in these 3 groups, being 56%, 70% and 78%, respectively.

Vaccine efficacy for the Oxford/AstraZeneca vaccine did increase by expanding the dose interval to 12 weeks. The corollary is that during those 12 weeks between the first and second dose, people are not protected as well.

Answer 2

It's not too clear what the claim or the question is here, but "higher" isn't as clear cut as you might think. I've managed to dig up again the ref I had read one point on this... but keep in mind that there has been no actual testing these alternative against each other in terms of infection rates or other "real world" outcomes. Rather the data we have had so far is antibodies or T-cells count, i.e. lab-based comparisons. And while antibody counts where higher for the longer interval/schedule, cellular immune response parameters were worse for the longer schedule::

It is the first direct comparison of the immune response in any age group between those given the second Pfizer vaccine at a three-week interval and those at a 12-week interval. [...]

The research found that extending the second dose interval to 12 weeks increased the peak SARS-CoV-2 spike specific antibody response 3.5-fold. This is compared to those who had the second vaccine at three weeks.

On the other hand, what didn't make the headline but is included in the same press release for this study:

The team found that within the three-week interval group, 60% had a confirmed cellular response at two to three weeks following the second vaccine. Although this fell to only 15% eight to nine weeks later.

The proportion of participants showing a cellular response in the 12-week interval group was only 8% at five to six weeks after the first vaccine. This rose to 31% two to three weeks after the second vaccine. Research is required to further explore these variations in responses.

So this could mean less long-term protection from the extended schedule as the cellular response (which was basically halved in probability for the longer schedule) is usually what is thought to matter in that long-term protection regard... quoting from another study, on primates:

Finally, the researchers tested whether immune cells called T cells play a role in long-term immunity to the virus. They used a drug to deplete T cells in five monkeys that had recovered from SARS-CoV-2, then re-exposed them to the virus. All had evidence of reinfection in the nose, and one had virus in its lungs. In contrast, monkeys with active T cells successfully fought off reinfection.

Antibodies initially produced by the body after infection had started to drop during this period. This finding suggests that T cells are needed for long-term protection from the virus.

But immunology is a complex science and the long-term waters haven't been tested with Covid-19, never mind variants, in this regard.