COVID-19 breakthrough infections: Where does vaccine stand?

Amidst the optimism from COVID-19 vaccine roll-out, the irrepressible yearning for normalcy is unmistakable. People are starting to drop their guard, thronging malls, and snapping up cruise tickets as soon as they become available. 

“We were in a state of euphoria about the high efficacy of several COVID-19 vaccines against the original virus, but then [our new] study threw us a curve-ball,” said Professor Shabir Madhi from the University of the Witwatersrand, Johannesburg, who led the Wits-VIDA COVID trial on ChAdOx1 nCoV19 vaccine in South Africa, where the B.1.351 strain predominates.

“In this study, we found that two doses of ChAdOx1 nCoV19 had no efficacy against nonhospitalized mild to moderate COVID-19, mainly due to the B.1.351 variant,” he stated.  

Meanwhile, emerging variants of concern (VOC) of SARS-CoV-2, in particular the UK B.1.1.7 strain, the South Africa B.1.351 strain, and the Brazil P.1 strain, have evolved to become the predominant circulating strains of SARS-CoV-2 in many countries. Elsewhere in the world, hospitals were woefully overwhelmed, with daily high of COVID-19 cases and deaths being set weeks after weeks in Brazil and India.

The pandemic was “growing exponentially” with more than 4.4 million new cases documented globally over the first week of April — so much so that the WHO technical lead for COVID-19, Dr Maria Van Kerkhove, proclaimed “we’re in a critical point of the pandemic … This is not the situation we want to be in 16 months into a pandemic where we have proven control measures.” 

A rude awakening

Researchers had an inkling that mutations harboured by the B.1.1.7 and B.1.351 strains could compromise the efficacy of the first-generation COVID-19 vaccines, which were designed to target the original SARS-CoV-2 virus. Protection against these variants was reduced by several folds compared with nonvariants, based on pseudovirus neutralization assay using serum samples of vaccinated individuals.

However, there were no data on how the in vitro observation will play out in humans in the real-world setting.  

The alarm was first raised by the landmark Wits-VIDA COVID trial, which enrolled 2,026 adults (median age 30 years, 56.5 percent male) in South Africa. The participants were generally healthy young adults free of HIV. Randomization was done 1:1 to either two doses of ChAdOx1 nCoV-19 vaccine or saline-containing placebo, given 21–35 days apart. [N Engl J Med 2021;doi:10.1056/NEJMoa2102214]

Vaccine efficacy was 21.9 percent (95 percent confidence interval [CI], -49.9 to 59.8), with no significant differences in the rates of mild-to-moderate COVID-19 illness between the vaccinated group vs the control group (2.5 percent vs 3.2 percent). This was in contrast to an overall vaccine efficacy of 66.7 percent originally reported ≥14 days after the second vaccine dose, before the B.1.351 and P.1 variants emerged. [Lancet 2021;397:881-891]

Among the COVID-19 cases with sequencing data available (n=41), 95.1 percent were attributed to the B.1.351 variant. A secondary analysis revealed that the vaccine efficacy against this variant was 10.4 percent (95 percent CI, -76.8 to 54.8).         

“[The findings] are truly a turning point in COVID-19 vaccine development — and a rude awakening,” said Madhi. “[This] study has alerted the world to the fact that second generation COVID-19 vaccines will be required to provide protection against inevitable and persistent SARS-CoV-2 variants.”

“Despite the disappointing finding that the ChAdOx1 nCoV-19 vaccine did not protect against mild COVID-19 infection [due to] the B.1.351 variant … our research makes a compelling case for the development of a second-generation vaccines worldwide,” he highlighted.

Vaccine reality

“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,” explained Madhi and co-authors.

“Although efforts to develop second-generation COVID-19 vaccines targeted against B.1.351 and P1-like variants are under way, the only COVID-19 vaccines likely to be available for most of 2021 have been formulated against the original virus,” they continued.

While the two mRNA vaccines (Moderna’s mRNA-1273 and Pfizer-BioNTech's BNT162b2 vaccines) held up well against the B.1.1.7 variant, their neutralization activity against the B.1.351 variant was dented by a factor of 8.6 and 6.5, respectively, based on results of pseudovirus neutralization assay. [bioRxiv (Preprint) 2021;doi:10.1101/2021.01.25.428137; Science 2021;371:1152-1153; N Engl J Med 2021;doi:10.1056/NEJMc2102017]

In a real-world study of BNT162b2-vaccinated individuals in Israel, the B.1.351 variant was able to evade vaccine-induced immunity and caused COVID-19 diseases — known as breakthrough infections — even after they had been fully vaccinated (referring to those tested ≥1 week following the second dose). [medRxiv (Preprint) 2021;doi:10.1101/2021.04.06.21254882]  

Among the participants who developed COVID-19, fully-vaccinated cases were eight times more likely to be caused by the B.1.351 variant than the cases observed in unvaccinated individuals (5.4 percent vs 0.7 percent; odds ratio, 8:1).

Meanwhile, cases occurring in partially vaccinated individuals (ie, infections occurring between 2 weeks after the first dose to 1 week after the second dose) were more likely to be due to the B.1.1.7 variant compared with unvaccinated cases (odds ratio, 26:10).

“These results are generally aligned with those from in vitro neutralization assays that have shown a large reduction in neutralization against B.1.351, and little to no reduction against B.1.1.7 in fully vaccinated individuals,” the researchers pointed out.

“Nevertheless, the B.1.351 incidence in Israel to-date remains low and vaccine effectiveness remains high against B.1.1.7, among those fully vaccinated,” they concluded. “These results overall suggest that vaccine breakthrough infection is more frequent with both VOCs, yet a combination of mass-vaccination with two doses coupled with non-pharmaceutical interventions [can] contain their spread.”

The breakthrough infections might have occurred as a result of immune evasions or ability to generate higher viral loads, according to the researchers.

However, there is no data on whether the PCR-positive cases detected were mild/asymptomatic or severe COVID-19 in the Israel study.   

Protection against severe disease
“There are always breakthroughs regardless of what the efficacy of the vaccine is,” said the US White House chief medical advisor Dr Anthony Fauci during a press briefing. “Even if a vaccine fails to protect against infection, it often protects against serious disease.”

Concurring with Fauci’s view, Madhi said, “While the the ChAdOx1 nCoV-19 vaccine — like many other first-generation COVID-19 vaccines — is unlikely to interrupt transmission of SARS-CoV-2 or protect against mild infection from variants like B.1.351, these first-generation vaccines could still provide the only sustainable option to prevent flooding our hospitals with severe COVID-19 cases, and to mitigate COVID-19 deaths once the third wave hits.”

“Our results emphasize the importance of tracking viral variants in a rigorous framework and of increasing vaccination, which we conclude is the safest and most effective means of preventing the onwards spread of B.1.351 and other possible future VOCs,” urged researchers of the Israel study.