The government of Canada has opted to prolong the second COVID-19 vaccination to 16 weeks after the first dose due to a limited vaccine supply. The decision was based on a recommendation from the National Advisory Committee on Immunization (NACI; www.canada.ca/en/public-health/services/immunization/national-advisory-committee-on-immunization-naci/recommendations-use-covid-19-vaccines.html#b1). The rationale is that administering one dose to a wider population will have a greater impact on severe COVID outcomes than giving the required two doses to fewer people. This raises the question: what are the benefits and risks of this partial-immunity approach?
The mRNA vaccines (Pfizer-BioNTech, Moderna) were tested and approved with a 21-day and 28-day dosing schedule. It should be noted that this schedule, approved by Health Canada, may not be optimal for stimulating an immune response; it was used primarily to produce more rapid trial results. The dosing interval for the AstraZeneca vaccine is 4-12 weeks based on the results of its clinical trial; efficacy was higher (65.6%) when doses were >8 weeks apart (Voysey et al. Lancet 2021;397:99-111).
There are conflicting data on the efficacy of a single vaccine dose. A phase IV study in Israel reported that efficacy (defined as prevention of COVID-19 disease) after the first dose of the Pfizer vaccine was 51% up to 24 days after immunization; the relative risk reduction was lower (44.5%) in subjects aged >60 years (Chodick et al. medRx preprint, 29 January 2021. https://doi.org/10.1101/2021.01.27.21250612).
Higher efficacy rates of 85% with the Pfizer vaccine and 94% with the AstraZeneca vaccine at 28-34 days post-vaccination were reported in a Scottish study. However, efficacy in this study was defined as COVID-related hospitalizations rather than prevention of COVID (Vasileiou & Simpson. Lancet preprint, 19 February 2021. https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3789264).
A math-based medicine approach has suggested that rolling out a first dose is more efficient and will produce better outcomes provided that the efficacy of that first vaccination is >50% (Harizi et al. medRx preprint, 26 March 2021. www.medrxiv.org/content/10.1101/2021.02.13.21251652v2.full.pdf). However, the model does not consider the durability of the immune response to the first dose, or the declining efficacy as variant strains emerge.
A number of one-dose studies have published preliminary results, with the caveats that a sufficient immune response has not been defined, and how that response should be assessed has not been determined. Most studies have reported neutralizing antibody levels, but their conclusions have been conflicting. The neutralizing antibody response with the Pfizer vaccine on day 21 after the first dose was modest, notably in patients aged 65-85 years (Walsh et al. N Engl J Med 2020;383:2439-2450). A separate study reported substantial differences in the antibody response after a first dose: geometric mean neutralization titres were an order of magnitude lower in subjects aged >80 years compared to younger adults (Collier et al. medRx preprint, 5 February 2021. www.medrxiv.org/content/10.1101/2021.02.03.21251054v1.full.pdf).
In the phase I/II study of the Pfizer vaccine, receptor binding domain (RBD)-binding IgG concentrations and CoV-2 neutralizing titres at 21 days after the first dose were also reported to be low (geometric mean concentration 534-1778 U/mL), increasing to 4813 to 27,872 U/mL only after the second dose (Mulligan et al. Nature 2020;586:589-593. www.nature.com/articles/s41586-020-2639-4.pdf). However, RBD-binding IgG titres were not substantially lower than what was seen in patients who had recovered from COVID-19 or had received convalescent serum (602 U/mL). It has not been determined if antibody levels following a single dose will be sustained for up to 16 weeks, or if delaying the second dose will impair the overall vaccine efficacy.
The strategy of delaying the second dose appears to be less defensible for at-risk groups. As noted previously, the antibody response to one dose is substantially lower for patients aged >65 years. Moreover, cancer patients do not appear to mount an adequate immune response to a single dose of Pfizer vaccine, according to the results of a UK study (Monin-Aldama et al. medRx preprint, 17 March 2021. www.medrxiv.org/content/10.1101/2021.03.17.21253131v1.full.pdf). In assessing anti-S protein IgG titres, 39% of patients with solid tumours and only 13% of patients with hematologic malignancies were classified as responders compared to 97% of healthy controls. A non-response was correlated with B cell numbers: median counts were 5,040 cells/mL for hematologic cancer non-responders, 34,680 cells/mL for solid-tumour non-responders, and 87,840 to 225,020 cells/mL for responders). The group also reported an impaired T cell response following a single vaccination. A fluorospot assay was used to identify T cells secreting interferon-gamma and/or IL-12 in response to spike peptides stimulating an MHC class I (CD8+ T cells) and MHC class II (CD4+ T cells) response. The T cell response was somewhat impaired in oncologic patients compared to healthy controls; interestingly, some T cell responders were serological non-responders, which may be due in part to the treatments they had received, such as anti-CD20 agents and BTK inhibitors. However, RBD reactivity was rare, which may indicate that the T cell response was to coronaviruses rather than specific to CoV-2.
While studies are ongoing, the data thus far suggest that the partial immunity obtained from a single vaccination may be sufficient to prevent severe COVID outcomes in most individuals, but may not be sufficient for at-risk groups, such as the elderly and patients who are immunocompromised or on a medication that depletes B and/or T cells.
Perhaps a more concerning peril of partial immunization is the risk of emergent variant strains of CoV-2. This issue will be addressed in Part 2.