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Clinical Context

Although vaccination against COVID-19 is a cornerstone of the public health response against the pandemic, recent data have demonstrated the limitations of vaccines, including waning efficacy over time and weaker efficacy against new variants of SARS-CoV-2. Still, an important strength of these vaccines has been their efficacy in the prevention of severe COVID-19, in particular. A previous study by the authors of the current research highlights these themes, using database results from the United Kingdom. Their research was published in the January 27 issue of the New England Journal of Medicine.^[1]

Vaccine efficacy against the delta variant of SARS-CoV-2 waned to 44.3% for the ChAdOx1 vaccine (AstraZeneca Pharmaceuticals LP), to 71.5% for the mRNA-1273 (Moderna) vaccine, and to 66.3% for the BNT162b2 vaccine (Pfizer Inc./BioNTech) at 20 weeks after the second dose; however, the vaccines’ respective protective rate against hospitalization remained high 20 weeks after the second dose. Unfortunately, persons at age 65 years and older experienced the greatest waning in vaccine efficacy.

How did vaccines perform in the prevention of infection with the omicron variant? The current study by Andrews and colleagues addresses this question.

Study Synopsis and Perspective

The currently available 2-dose COVID-19 vaccines were not effective in preventing symptomatic disease caused by the omicron variant, as determined according to data from more than 800,000 omicron-infected individuals.

Early laboratory data suggested a substantially lower neutralizing antibody response to the omicron variant compared with both the original COVID-19 strain and the delta variant, wrote Nick Andrews, PhD, of the United Kingdom Health Security Agency, and colleagues.

Vaccines have shown high levels of effectiveness against symptomatic disease and severe disease and death resulting from the original COVID-19 virus and the alpha variant and modest effectiveness against the beta and delta variants, they said.

"Neutralizing antibodies correlate with protection against reinfection and vaccine effectiveness against infection; therefore, reduced vaccine effectiveness against the omicron variant is anticipated on the basis of these early laboratory findings," they explained.

In a study published online March 2 in the New England Journal of Medicine,^[2] the researchers identified 886,774 adults aged 18 years and older who had been infected with the omicron variant, 204,154 who had been infected with the delta variant, and 1,572,621 symptomatic control patients who tested negative for COVID-19 between November 27, 2021 and January 12, 2022. The participants had been vaccinated with 2 doses of BNT162b2, (Pfizer-–BioNTech), ChAdOx1 nCoV-19, (AstraZeneca), or mRNA-1273 (Moderna) vaccine, plus a booster given at least 175 days after a second dose, after September 13, 2021.

Vaccine effectiveness was calculated after primary immunization at weeks 2 to 4, 5 to 9, 10 to 14, 15 to 19, 20 to 24, and 25 or longer after the second dose, and at 2 to 4, 5 to 9, and 10 or more weeks after boosters.

Omicron infections that occurred starting 14 or more days after a booster occurred a median of 39 days after the booster.

"Vaccine effectiveness was lower for the omicron variant than for the delta variant at all intervals after vaccination and for all combinations of primary courses and booster doses investigated," the researchers wrote.

Individuals who received 2 doses of ChAdOx1 nCoV-19 doses had almost no protection against symptomatic disease caused by Omicron from 20 to 24 weeks after the second dose. For individuals who received 2 doses of BNT162b2, effectiveness was 65.5% 2 to 4 weeks after the second dose, but effectiveness declined to 15.4% after 15 to 19 weeks and to 8.8% after 25 or more weeks. For individuals who received 2 doses of mRNA-1273, vaccine effectiveness was 75.1% after 2 to 4 weeks, but effectiveness declined to 14.9% after 25 or more weeks.

Boosters created a short-term improvement in vaccine effectiveness against the omicron variant, but this effect also declined over time.

Among individuals who received primary doses of ChAdOx1 nCoV-19, vaccine effectiveness increased to 62.4% 2 to 4 weeks after a BNT162b2 booster, then declined to 39.6% after 10 or more weeks. After an mRNA-1273 booster, vaccine effectiveness increased to 70.1% at 2 to 4 weeks and decreased to 60.9% at 5 to 9 weeks.

Among individuals who received primary doses of BNT162b2, vaccine effectiveness increased to 67.2% 2 to 4 weeks after a BNT162b2 booster, then declined to 45.7% at 10 or more weeks. After an mRNA-1273 booster, vaccine effectiveness increased to 73.9% at 2 to 4 weeks, then declined to 64.4% at 5 to 9 weeks.

Among individuals who received primary doses of mRNA-1273, vaccine effectiveness increased to 64.9% 2 to 4 weeks after a BNT162b2 booster and 66.3% 2 to 4 weeks after an mRNA-1273 booster.

The study findings were limited by potential confounding from study participants who had traveled and may have had different levels of vaccine coverage and by the inability to break down estimates on the basis of age and clinical risk that might affect vaccine effectiveness, the researchers noted. Other limitations include a lack of data on vaccine effectiveness for a longer period after boosters, they said.

Still, the results are consistent with neutralization data for the omicron variant in studies from the United Kingdom, South Africa, and Germany, they wrote.

"Our findings support maximizing coverage with third doses of vaccine in highly vaccinated populations such as in the United Kingdom. Further follow-up will be needed to assess protection against severe disease and the duration of protection after booster vaccination," they concluded.

Paul Offit, MD, of the University of Pennsylvania, Philadelphia, addressed the topic of vaccine effectiveness in an op-ed published on March 4 in the Philadelphia Inquirer. ^[3] The following is adapted from the op-ed, with his permission.

"The goal of the COVID vaccine -- as is true for all vaccines -- is to prevent serious illness," Offit wrote.

"For most people with normal immune systems, two doses of mRNA vaccines appear to do exactly that. But not everyone," wrote Offit, who serves as director of the Vaccine Education Center at the Children's Hospital of Philadelphia and also serves on the FDA's Vaccine Advisory Committee.

"Three doses are required to induce high levels of protection against serious illness for people over 65 years of age or for people with other conditions that make them vulnerable, which can be anything from being overweight to having cancer. For people who are immune compromised, four doses might be required," he noted.

Frequent vaccine boosting, although it may help prevent milder cases of COVID-19, such as those seen with the omicron variant, is impractical, Offit emphasized. Instead, a newer, variant-specific vaccine might be needed if a variant emerges that overrides the protection against severe disease currently afforded by the available vaccines, he said.

"But we're not there yet. For now, we are going to have to realize that it is virtually impossible to prevent mild COVID without frequent boosting. So, let's learn to accept that the goal of COVID vaccines is to prevent severe and not mild illness and stop talking about frequent boosting. Otherwise, we will never be able to live our lives as before," he wrote.

The study was supported by the UK Health Security Agency. The researchers and Offit have disclosed no relevant financial relationships.

Clinical Implications

• A previous study by Andrews and colleagues found significant waning of efficacy for the 2-dose ChAdOx1 and BNT162b2 vaccines in preventing infection with the delta variant of SARS-CoV-2; however, 2 doses of either vaccine remained effective in the prevention of hospitalization. Waning of vaccine efficacy was most pronounced among older adults.
• The current study by Andrews and colleagues finds that vaccine efficacy was weaker for the omicron vs delta variants of SARS-CoV-2, with the best results for the mRNA-based vaccines. A 2-dose vaccine series completed ≥ 25 weeks was nearly completely ineffective in the prevention of the omicron variant, but the booster dose significantly raised protection against omicron.
• Implications for the healthcare team: The healthcare team should promote vaccination and other nonpharmacologic prophylaxis, including masking and physical distancing, against COVID-19 among individuals at high risk for complications.

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