WHO says AZ second dose could be effective after 6-month interval; discourages mix-and-match schedule

The World Health Organization (WHO) in a technical note published on 26 May discouraged mix-and-match schedules until the publication of favourable data, stating that unpublished data showed strong anamnestic response even after an interval of six months between the two doses of the AstraZeneca vaccine.

The technical note looked at the implications of delayed shipments for the AstraZeneca vaccine on the second dose, which Sri Lanka is currently struggling with. According to WHO, there is no need to restart the full course of vaccination if the second dose is not administered within the recommended eight to 12-week interval.

“Unpublished data show a strong anamnestic response even after an interval between doses of six months, indicating that the first dose provides robust immunological priming,” the statement read.

While explaining that there is little information on clinical protection with only one dose of the vaccine beyond 12 weeks, WHO stated that binding antibodies against the COVID-19 spike protein have only a slow decay over a period of six months. 

Variants of concern

However, when considering variants of concern (VOC), WHO states that emerging evidence shows a protective efficacy of AstraZeneca vaccine against the B.1.1.7 UK variant, but that very little data is available on efficacy against clinical disease for the B.1.351 South African variant.

According to WHO, studies of antibodies following immunisation with the AstraZeneca vaccine against B.1.351 (South Africa), P.1 (Brazil) and B.1.617 (India) show that neutralising activity is lower than against the ancestral strain. “This information is relevant because single dose vaccination results in lower antibody titres. Whether this translates into lower effectiveness against VOCs is currently unknown,” WHO states.

The World Health Organization says that it is possible that effectiveness against mild-moderate disease diminishes, but is more preserved against severe disease. 

Mix-and-match schedule

Given the inability to determine the effectiveness of a single dose against variants of concern and shortages of the AstraZeneca COVID-19 vaccine, WHO also explored the possibility of using a different vaccine as the second dose.

“As all currently authorised COVID-19 vaccines comprise the same target (spike protein), it would be expected that a heterologous (mix and match) COVID-19 vaccine as a second dose would boost the immune response,” the technical note read, adding that countries like Germany, France, Sweden, Finland, Denmark and Norway have introduced mix and match schedules.

However, data from only two mix and match studies are currently available in preprint, one of which is a UK study investigating the use of either AstraZeneca or Pfizer for both doses and the use of the two vaccines in a mixed schedule.

According to WHO, symptoms experienced by trial participants who received a mixed schedule included increased rates of fever, fatigue, chills and headaches when compared to participants that received the same vaccine for both doses.

Immunogenicity results from this study are not yet available, WHO states, adding that evidence of protection from mix and match schedules that include the AstraZeneca vaccine on SARS-CoV-2 infection and COVID-19 disease are also not available.

“Given the absence of data on immunogenicity and the increase in reactogenicity when switching the second dose from ChAdOx1-S [recombinant] vaccine to the Pfizer BNT162b2 vaccine, countries are advised to wait for favourable immunogenicity data from the interchangeability studies before deciding on such a mix and match schedule,” the technical note reads.

WHO adds that further studies with other vaccine combinations with the AstraZeneca vaccine in a mix and match schedule have not yet been completed. 

Factors to consider following vaccine availability

When AstraZeneca vaccines become available, a question arises on administration. Should available vaccines be used to administer the second dose or should they be used to further increase vaccination coverage by administering the first dose to more persons?

According to WHO, various factors need to be considered when providing an answer to this question. In addition to vaccine performance issues, country-specific considerations are also a deciding factor.

These considerations include the severity of the COVID-19 epidemiological situation, access to health services, progress on vaccine coverage of the high-priority populations, the circulation of specific VOCs, and programmatic and communication issues.

“Countries can prevent more deaths and hospitalisations at a population level if more people in the higher priority groups (e.g., older adults and health workers) are vaccinated, even with just one dose, than they can achieve by using existing vaccine supply for second dose administration of these very same groups in smaller numbers,” WHO states.

The World Health Organization adds that, for settings with substantial circulation of VOCs which have been shown to have reduced single dose effectiveness, the importance of providing the most vulnerable groups with two doses must be considered.

“If circulating VOC result in a substantially lower one-dose efficacy relative to two doses, and/or if clinical protection wanes very quickly, then modelling evidence supports prioritisation of delivery of second doses to the high-priority groups instead of providing a single dose to all adults,” WHO states.

However, WHO adds that this note may be updated in the future based on emerging evidence on vaccine effectiveness, duration of protection, and modelling in various country settings.