By Sally Robertson, B.Sc.Sep 22 2021

Researchers in Canada, Italy, and the United States have encouraged extending the interval time between two doses of Pfizer-BioNTech’s coronavirus disease 2019 (COVID-19) vaccine among individuals who have not previously been infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

The team found that while administration of a second dose at 16 weeks did not significantly improve humoral (antibody) responses among individuals who were infected prior to the first dose, it significantly enhanced these responses among infection-naïve individuals.

Andres Finzi from the CHUM Research Centre in Montreal, Quebec, and colleagues say the findings should help to alleviate concerns that an extended interval between doses might affect the efficacy of vaccination.

A pre-print version of the research paper is available on the medRxiv* server, while the article undergoes peer view.

More about extending the vaccination interval time

Since the COVID-19 outbreak began in late December 2019, several effective vaccines against the causative agent SARS-CoV-2 have been approved for use in many countries, including Pfizer-BioNTech’s BNT162b2 vaccine.

This vaccine targets the viral spike protein that mediates the infection process when it binds to host cells. Therefore, this spike is a primary target of antibodies following vaccination or natural infection.

The approved standard regimen for BNT162b2 vaccination involves two doses administered 3 to 4 weeks apart.

However, during the initial phase of vaccination rollout in the winter and spring of 2021, vaccine supply shortages prompted some public health authorities to extend this interval to maximize the number of individuals who could be immunized.

This strategy was supported by studies indicating that a single dose confers around 90% protection just two weeks following vaccination.

Elicitation of RBD- and Spike-specific antibodies in SARS-CoV-2 naïve and previously-infected individuals. (A) SARS-CoV-2 vaccine cohort design. (B-E) Indirect ELISA was performed by incubating plasma samples from naïve and PI donors collected at V0, V1, V2 and V3 with recombinant SARS-CoV-2 RBD protein. Anti-RBD Ab binding was detected using HRP-conjugated (B) anti human IgM+IgG+IgA (C) anti-human IgM, (D) anti-human IgG, or (E) anti-human IgA. Relative light unit (RLU) values obtained with BSA (negative control) were subtracted and further normalized to the signal obtained with the anti-RBD CR3022 mAb present in each plate. (F-I) Cell based ELISA was performed by incubating plasma samples from naïve and PI donors collected at V0, V1, V2 and V3 with HOS cells expressing full-length SARS-CoV-2 S. Anti-S Ab binding was detected using HRP-conjugated (F) anti-human IgM+IgG+IgA (G) anti-human IgM, (H) anti human IgG, or (I) anti-human IgA. RLU values obtained with parental HOS (negative control) were subtracted and further normalized to the signal obtained with the CR3022 mAb present in each plate. Naïve and PI donors with a long interval between the two doses are represented by red and black points respectively and PI donors who received just one dose by blue points. (Left panels) Each curve represents the normalized RLUs obtained with the plasma of one donor at every time point. Mean of each group is represented by a bold line. The time of vaccine dose injections is indicated by black triangles. (Right panels) Plasma samples were grouped in different time points (V0, V1, V2 and V3). Undetectable measures are represented as white symbols, and limits of detection are plotted. Error bars indicate means ± SEM. (* P < 0.05; ** P < 0.01; *** P < 0.001; **** P < 0.0001; ns, non-significant).

Concerns about the impact on vaccine efficacy

However, this decision led to concerns about the impact on vaccine efficacy, particularly in the context of the SARS-CoV-2 variants of concern (VOCs) and interest (VOIs) that have rapidly emerged and spread worldwide.

These variants are more transmissible than previously circulating strains and, in some cases, more resistant to the neutralizing antibodies generated following vaccination.

For example, the spike mutation D614G that arose early on in the pandemic is now present in almost all circulating strains, and the B.1.1.7 (alpha) variant that emerged in late 2020 soon became the predominant strain globally.

More recently, the highly transmissible B.1.617.2 (delta) lineage that emerged in India in the spring of 2021 has now become the dominant strain in several countries.

Although several vaccines have demonstrated high efficacy in protecting against severe disease caused by these variants, some have also been shown to generate less effective neutralizing antibody responses.

However, the majority of these studies analyzed plasma samples collected from individuals vaccinated on the short (3 to 4 weeks) dosing interval regimen.

“Little is known about vaccine-elicited immune responses with longer dose intervals,” says Finzi and colleagues.

What did the researchers do?

The team assessed vaccine-elicited humoral responses among 22 SARS-CoV-2-naïve individuals and 11 previously infected individuals who received two doses of Pfizer-BioNTech’s BNT162b2 vaccine separated by an interval of 16 weeks. The previously infected participants had tested positive for SARS-CoV-2 around nine months before they received the first dose.

Blood samples were analyzed longitudinally for antibody binding, Fc-mediated effector functions and neutralizing activity against the D614G strain, several VOCs and VOIs, and SARS-CoV-1.

What did they find?

In the SARS-CoV-2-naïve group, immunization elicited antibodies with weak neutralizing activity but strong Fc-mediated functions three weeks following the first dose.

These responses declined over the following weeks. However, administration of a second dose 16 weeks later significantly enhanced these responses.

Notably, neutralizing activity against some VOCs, VOIs and even the divergent SARS- CoV-1 was significantly increased.

What about the previously infected individuals?

Several studies have shown that vaccinating previously infected individuals elicits strong humoral responses.

In agreement with these studies, the researchers found that the first vaccine dose induced strong humoral responses among the previously infected participants that remained relatively stable over time.

However, a second dose administered 16 weeks later did not significantly enhance any of these responses.

The team says this finding indicates that previously infected individuals reach peak immunity following the first dose of BNT162b2, suggesting that a second dose could possibly be delayed beyond sixteen weeks in this population group.

Modifying the interval dose should be considered

The researchers advise that bringing the COVID-19 pandemic to an end will require rapid vaccination of the global population, including in countries where vaccines are scarce.

“Modifying the interval at which the two doses are administered might be an important factor to take into account,” they suggest.

*Important Notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.