The results of a double-blind, randomized, multisite placebo-controlled trial that was conducted in South Africa show that Oxford’s ChAdOx1 nCoV-19 (AZD1222) vaccine has no efficacy against the B.1.351 variant in preventing mild-to-moderate coronavirus disease 2019 (COVID-19), and shows reduced neutralization properties of developed antibodies. The findings are published in the New England Journal of Medicine.

The speed of vaccine development against COVID-19 has been unprecedented, with six of them already authorized for emergency usage. One of the more pervasive ones is ChAdOx1 nCoV-19 (AZD1222) from the University of Oxford and AstraZeneca, which contains a replication-deficient adenoviral vector from a chimpanzee with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) surface glycoprotein antigen sequence.

However, the virus quickly racked up mutations within the receptor-binding domain (RBD) and the N-terminal domain (NTD) of the spike glycoprotein, which are two primary targets of the antibody response against SARS-CoV-2 prompted by the vaccines.

The B.1.1.7 (or N501Y.V1) lineage, which was initially identified in the United Kingdom, includes the N501Y mutation linked to increased affinity of the virus to the receptor angiotensin-converting enzyme 2 (ACE2), but also increased transmissibility for up to 53%.

Moreover, the B.1.351 (N501Y.V2) lineage, originally found in South Africa, harbors three RBD mutations and five supplementary NTD mutations. This is definitely a problem, as studies have shown that 48% of serum samples from convalescent donors that were infected with the prototype virus were unable to neutralize this mutated strain, as determined by a spike-pseudovirus neutralization assay.

This is why this interim analysis, conducted by the members of the Wits–VIDA COVID Group, aimed to address not only standard objectives of vaccine safety and efficacy but also efficacy correlates that are specifically steered against the B.1.351 viral variant.

Setting up the trial

In order to do so, this large research group conducted a randomized, double-blind, multicenter controlled trial to test the AZD1222 vaccine in people not infected with the human immunodeficiency virus (HIV) in South Africa. The main exclusion criteria were the presence of HIV, previous or current COVID-19, a history of anaphylaxis related to vaccines, and morbid obesity.

Selected participants were aged between 18 and 65 years of age and assigned to receive two doses of vaccine (in a 1:1 ratio) containing either 5 × 10¹⁰ viral particles or placebo (consisting of saline or 0.9% sodium chloride solution) 21 to 35 days apart.

After the second dose, serum specimens were taken from 25 participants and subsequently tested by live-virus and pseudovirus neutralization assays against the original D614G viral strain and the B.1.351 variant. Safety and efficacy against symptomatic and laboratory-established COVID-19 were primary endpoints. Moreover, the University of Oxford was responsible for overseeing the whole trial.

Compromised neutralization response

In this interim report, both live-virus and pseudovirus neutralization assays demonstrated greater resistance to the B.1.351 variant in serum specimens from vaccine recipients when compared to those from placebo recipients. Mild-to-moderate COVID-19 was observed in 3.2% of placebo recipients and 2.5% of vaccine recipients, representing an efficacy of 21.9%.

Nevertheless, both neutralization assay experiments provide proof of reduced or repudiated vaccine-induced antibody neutralization against the B.1.351 variant, akin to the responses observed in vaccinated participants in the research endeavors conducted in Brazil and the United Kingdom.

Albeit we still do not know the exact degree of attenuation that can compromise an effective neutralizing antibody response in humans, the highest degree of neutralization against B.1.351 in a vaccinated individual in live-virus neutralization assay was a 1:20 dilution, while the highest enduring titer against B.1.351 was less than 1:200 in the pseudovirus neutralization assay.

Vaccine as a selection pressure for SARS-CoV-2

A question mark that remained unanswered after this trial is whether the enhanced antibody response that is observed after a longer interval between the first and second doses of the vaccine might confer improved residual neutralizing activity against the South African variant when compared to these results.

“Relative resistance to human neutralizing antibody responses is expected to be a feature of the pandemic coronavirus in the years ahead, as a result of pressure on the virus to select for variants that can transmit despite immunity after natural infection or vaccination,” caution study authors.

Finally, all deliberations on the efficacy of the AZD1222 vaccine also need to be put in the context of continuous worldwide spread and community transmission of the B.1.351 variant and the potential rise of other SARS-CoV-2 strains that incorporate similar mutations.

Written by

Dr. Tomislav Meštrović

Dr. Tomislav Meštrović is a medical doctor (MD) with a Ph.D. in biomedical and health sciences, specialist in the field of clinical microbiology, and an Assistant Professor at Croatia's youngest university – University North. In addition to his interest in clinical, research and lecturing activities, his immense passion for medical writing and scientific communication goes back to his student days. He enjoys contributing back to the community. In his spare time, Tomislav is a movie buff and an avid traveler.