An updated look at the 16-week window between doses of vaccines in BC for COVID-19

Issue: BCMJ, vol. 63, No. 3, April 2021, Pages 102-103 Letters COVID-19
By: Tonia Tauh, MD, FRCPC Michelle Mozel, MSc Paula Meyler, MD, FRCPC Susan M. Lee, MD, FRCPC, MAS

In accordance with new recommendations from the National Advisory Committee on Immunization, British Columbia has extended the interval between first and second doses up to 16 weeks for all currently approved COVID-19 vaccines in Canada.[1] In light of this change—developed to maximize the number of individuals receiving their first doses of the COVID-19 vaccine—we have updated our review of the literature.

Real-world data have emerged from jurisdictions that extended their gap between the first and second doses.[2,3] The United Kingdom approached vaccination with a planned 12-week dosing gap. In a UK preprint report (not yet peer reviewed), 60% to 70% protection was achieved in adults over the age of 70 after only one dose of either the Pfizer-BioNTech or Oxford-AstraZeneca vaccine.[4] This protection was sustained up to the maximum follow-up period of 56 and 41 days respectively, albeit with limited numbers at the longer durations. Protection against symptomatic disease was further increased to 85% to 90% following the second dose of Pfizer-BioNTech vaccine.[5] Among those who were symptomatic, the risk of hospitalization and death was reduced by 44% and 51% respectively, after a single dose of Pfizer-BioNTech, compared to an unvaccinated group.[4] These data are encouraging when you consider that the UK variant (VOC 202012/01) was dominant during the study period.

There are also multiple reports confirming what was seen in clinical trials: protection begins around 2 weeks after dose 1 and is sustained thereafter for the duration studied.[5,6] Encouragingly, asymptomatic disease and viral loads also appear to be reduced after the first vaccination dose.[5] However, given that less than 4 months have passed since the vaccine was approved in any jurisdiction, longer-term data are not yet available. While there is biologic plausibility to surmise that these novel vaccines might provide months of protection like other protein-antigen based vaccines (e.g., HPV),[7,8] preprint data from Scotland show higher vaccine efficacy at day 28 to 34 compared to day 35 to 42 following a single dose of Pfizer-BioNTech or Oxford-AstraZeneca.[9] The significance of this, or whether there is a further decline in immunity beyond day 42, is not yet known.

A single vaccine dose clearly reduces COVID-19 infection, hospitalization, and death. When supplied to a wide enough population, transmission is also curtailed.[5] Although there is a lack of data to directly support a 16-week gap compared to shorter intervals, in the current setting of vaccine scarcity, it appears reasonable to accept the risk of an extended dosing interval in order to more rapidly provide protection to a greater proportion of the population. Vigilance will be key in determining whether this practice can continue safely while vaccine supply is limited; if the extended gap is found to put those waiting for dose 2 at excessive risk, then a shorter interval would need to be reconsidered. 
—Tonia Tauh, MD, FRCPC
—Michelle Mozel, MSc
—Paula Meyler, MD, FRCPC
—Susan M. Lee, MAS, MD, FRCPC
Royal Columbian Hospital Department of Anesthesia COVID-19 Working Group Research Team

This letter was submitted in response to “What is the evidence for extending the SARS-CoV-2 (COVID-19) vaccine dosing schedule?”

References

1.    Government of Canada. NACI rapid response: Extended dose intervals for COVID-19 vaccines to optimize early vaccine rollout and population protection in Canada. Accessed 3 March 2021. www.canada.ca/en/public-health/services/immunization/national-advisory-committee-on-immunization-naci/rapid-response-extended-dose-intervals-covid-19-vaccines-early-rollout-population-protection.html.

2.    BCCDC. Early findings show the first vaccine dose reduced the risk of COVID-19 by 80 per cent or more. Accessed Mar 3, 2021. www.bccdc.ca/about/news-stories/news-releases/2021/early-findings-show-the-first-vaccine-dose-reduced-the-risk-of-covid-19-by-80-per-cent-or-more.

3.    Joint Committee on Vaccination and Immunisation (UK). Optimising the COVID-19 vaccination programme for maximum short-term impact. Accessed 3 March 2021. https://app.box.com/s/uwwn2dv4o2d0ena726gf4403f3p2acnu.

4.    Bernal JL, Andrews N, Gower C, et al. Early effectiveness of COVID-19 vaccination with BNT162b2 mRNA vaccine and ChAdoX1 adenovirus vector vaccine on symptomatic disease, hospitalisations and mortality in older adults in England. medRxiv. Accessed 3 March 2021. www.medrxiv.org/content/10.1101/2021.03.01.21252652v1.

5.    Weekes M, Jones NK, Rivett L, et al. Single-dose BNT162b2 vaccine protects against asymptomatic SARS-CoV-2 infection. Authorea. Accessed 3 March 2021. www.authorea.com/users/332778/articles/509881-single-dose-bnt162b2-vaccine-protects-against-asymptomatic-sars-cov-2-infection?access_token=-hDTQsMUXcCPSpdZV_Lmpg.

6.    Dagan N, Barda N, Kepten E, et al. BCT162b2 mRNA Covid-19 vaccine in a nationwide mass vaccination setting. NEJM 2021. https://doi.org/10.1056/NEJMoa2101765.

7.    British Society for Immunology. British Society for Immunology statement on COVID-19 vaccine dosing schedules. Accessed 3 March 2021. www.immunology.org/policy-and-public-affairs/briefings-and-position-statements/COVID-19-vaccine-dosing-schedules.

8.    Kreimer AR, Sampson JN, Porras C, et al. Evaluation of durability of a single dose of the bivalent HPV vaccine: The CVT Trial. J Natl Cancer Inst 2020;112:1038-1046. 

9.    Vasileiou E, Simpson CR, Robertson C, et al. Effectiveness of first dose of COVID-19 vaccines against hospital admissions in Scotland: National prospective cohort study of 5.4 million people. Accessed 4 March 2021. www.ed.ac.uk/files/atoms/files/scotland_firstvaccinedata_preprint.pdf.

Tonia Tauh, MD, FRCPC, Michelle Mozel, MSc, Paula Meyler, MD, FRCPC, Susan M. Lee, MD, FRCPC, MAS. An updated look at the 16-week window between doses of vaccines in BC for COVID-19. BCMJ, Vol. 63, No. 3, April, 2021, Page(s) 102-103 - Letters, COVID-19.


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Mohammad Dar says: reply

This study is clearly showing that protection data beyond the interval of 42 days (i.e 6 weeks) between prime and booster dosing of Covid 19 vaccination is not available anywhere. Even 42 days interval is quite risky. So from where this interval of
16 weeks is coming ? In my opinion this practice of 16 week interval will jeopardize the motives and money and efforts invested on provision of Ist dose effects. There is no scientific data/evidence have been shown to justify this delayed interval.

jason fordham says: reply

None of the letters or papers I've seen have made any attempt to enumerate, let alone evaluate, the risks created by the extended 16 week interval. They only reference them, and say they are "acceptable".

One of the risks is more effective cultivation of antibody (and therefore vaccine) resistant variants. If the effectivity drops off, then the response could kill only the less resistant viruses, leaving the stronger to reproduce, passing on their resistance to future variants.

How is this risk "acceptable"? I do not see it, not at all. but the risk that the long interval between first and second doses will breed variants resistant to the spike protein antibodies is one that must be considered, not one that can be ignored.

Tracey says: reply

I fail to understand how the authors came to conclude that a 16 week gap between vaccines was reasonable based on the studies reported. Research, as reported here, has shown that vaccine efficacy begins to decrease at day 35. There is absolutely no evidence provided to support the assumption that immunity will be high enough to protect people for 16 weeks, or that the second dose will have the desired effect of increased immunity after that long a wait.

jason fordham says: reply

A meaningless recommendation without an evaluation of the risks
.
While the authors conclude:
.
> Although there is a lack of data to directly support a 16-week gap compared to shorter intervals,
> in the current setting of vaccine scarcity, it appears reasonable to accept the risk of an extended
> dosing interval in order to more rapidly provide protection to a greater proportion of the
> population.

there is no evaluation or even enumeration of the risks before conjuring the appearance of reasonableness out of nothing.
.
Siri Kadire MD et al writing for the NEJM (https://www.nejm.org/doi/full/10.1056/NEJMclde2101987, March 4) argue that a non-standard delay between doses may risk a lower effectiveness for the second dose - but their horizon is twelve weeks, not sixteen. As the present authors say, there is no evidence for sixteen weeks at all. One result may be that the gap does nothing but provide a false sense of security, possibly creating a population which needs a third vaccination, doesn't know it, and can't get that additional vaccine anyway. Meanwhile the virus continues to evolve.
.
My recollection of the history of the evolution of MRSA is that an insufficient defence against a hostile vector serves to select the stronger variants over the weaker. That creates a deathly significant risk here. It seems to me that a well-founded resolution to the issues before us all requires urgently eliminating the supply bottleneck by every means available, and adding delay could well be worse than doing nothing.

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