mRNA-1273's efficacy against SARS-CoV-2 Omicron and Delta variants

Multiple unique spike (S) protein mutations have been discovered in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron (B.1.1.529) variant that arose in December 2021, raising concerns regarding escape from naturally acquired or vaccine-elicited immunity. Vaccine-induced neutralizing activity against Omicron was found to be diminished in several in vitro experiments. When compared to wild-type SARS-CoV-2, sera from people who received two doses of mRNA coronavirus disease 2019 (COVID-19) vaccines, including mRNA-1273 (Moderna), exhibited significant reductions in neutralizing activity against Omicron. An mRNA-1273 booster, on the other hand, boosted neutralization activity against Omicron, though at a lesser level than wild-type.

According to authors "In a real-world scenario, we tested the efficacy of mRNA-1273 against the highly mutated Omicron variant in a socio-demographically heterogeneous population. The rapidly increasing number of Omicron-positive specimens suggested extraordinary transmissibility, raising questions about the protection provided by COVID-19 vaccinations that are currently authorized or licensed". 

"Our research shows that Vaccine effectiveness (VE) of two doses of mRNA-1273 against Delta infection, declines slowly, and the VE dosage against Omicron infection is insufficient, providing only limited protection of 44.0 percent within 3 months of vaccination and rapidly fading thereafter, consistent with our earlier findings. Furthermore, while the 3-dose VE against Delta infection is strong and long-lasting, it is lower against Omicron" author added. 

Nonetheless, the average point estimate (>50%) and lower bound of the 95 percent CI 130 (>30%) match the US FDA criteria for COVID-19 131 vaccine emergency use authorization. This level of VE is also comparable to the phase 3 clinical trial's 2-dose vaccine effectiveness against asymptomatic infection (63.0 percent [56.6–68.5 percent]). The VE of three doses of mRNA-1273 against Omicron infection is low in immunocompromised people.

While Omicron's 2-dose VE against hospitalization is lower than Delta's, both variants' 3-dose VE is about 100 percent effective against hospitalization. Although more research is needed, these findings imply that third (booster) doses may be required 6 months after dosage 2 in immunocompetent persons, and that three doses may be insufficient in immunocompromised individuals. Furthermore, the findings suggest that vaccinations may need to be adjusted on a regular basis to target circulating variations that have evolved to evade current vaccine-induced protection.

While there is limited historical evidence on the VE of 2 or 3 doses of mRNA-1273 vaccine against Omicron infection or hospitalization, a preliminary investigation from Denmark indicated an initial VE of 36.7 percent for 2 doses of mRNA-1273 against Omicron infection that quickly decreased, comparable to research findings.

Andrews and colleagues found waning 2-dose protection with an initial VE of 88 percent (65.9–95.8%) 2–9 weeks after dose 2 that declined to 34–37 percent (95 percent CIs ranging from –5 to 59.6 percent) 15 or more weeks after dose 2, but increased to 75.5 percent (56.1–86.3 percent) a median of 41 days (range 14–72 days) after a BNT162b2 booster.

Collie and colleagues discovered that two doses of BNT162b2 had a 70 percent VE against hospitalization during a proxy Omicron interval at least 14 days following dose 2. Following a first course of BNT162b2 vaccine, VE against Omicron infection was initially 70% after a BNT162b2 booster, declining to 45% after ten weeks, but remained about 70%–75% for up to nine weeks after an mRNA-1273 booster in England.

According to a rising number of reports, COVID-19 disease linked with Omicron is less severe than COVID-19 disease associated with Delta, resulting in a lower likelihood of hospitalization. This could be due to enhanced Omicron replication in the upper vs. lower respiratory tracts, which could lead to more efficient transmission and a higher number of hospitalizations overall. Booster immunization has the potential to reduce the number of patients admitted to hospitals and enhance clinical outcomes. While the sample size and follow-up duration in the study and others were insufficient to determine potential waning VE against Omicron infection, Their findings of fading VE against Omicron infection after dosage 3 of mRNA-1273 emphasize the necessity of monitoring VE against Omicron infection.

These findings were published in "Nature". The participants in this study came from a wide range of racial, cultural, and socioeconomic backgrounds in Southern California. It has various benefits and limitations, and it adds to recent findings on the efficacy of different COVID-19 vaccinations against Omicron infection.

First, the findings of test-negative case-control study may not be applicable to those who were not tested, such as those with weaker symptoms who may not seek testing. While there are a multitude of reasons for testing that could lead to biases, the team tried to account for sociodemographic variables, prior health care utilization, SARS-CoV-2 testing, and comorbidities in the models to minimize these biases. Although there was a chance of residual confounding or detection bias, it was unlikely to alter the study's conclusions.

While disease status misclassification could be a source of bias, researchers used a highly specific and sensitive RT-PCR assay that likely reduced misclassification and allowed us to track variant proportions using whole genome sequencing and SGTF analysis. Misclassification of vaccination status was also possible, however it was most likely minor and non-differential in terms of COVID-19 illness status. 

For four months before Omicron appeared in Southern California in December 2021, Delta accounted for 99 percent of variants. Furthermore, Delta and Omicron accounted for >99 percent of variations during the research period, and the BA.2 sub-lineage of Omicron was not found in any of the 1,383 specimens sequenced in this investigation. As a result, it's plausible to assume that during the study period, all variations with SGTF were Omicron and those without SGTF were Delta. Third, some immunocompetent people who received a third dose of mRNA-1273 before the Advisory Committee on Immunization Practices guideline of October 21, 2021, may have received a 100-g dosage rather than a 50-g booster dose.

However, because dosage information was not available from external vaccination records, the team was unable to examine the difference accurately. The number of hospitalized people included in the study was insufficient to establish firm conclusions about VE and the long-term effectiveness of three doses in preventing hospitalization. To assess the durability of both the 100-g and 50-g booster doses in preventing infection and hospitalization, a long-term follow-up of 200 days is required. Also, they did not test VE against infection, whether it was symptomatic or asymptomatic. However, they discovered a greater VE in the presence of COVID-19 hospitalization. Information on whether infections were symptomatic or asymptomatic was not readily available, save from saliva tests that were exclusively gathered in asymptomatic persons.

The VE of mRNA-1273 was found to be declining after two doses but high after three doses against Delta infection and lower after two and three doses against Omicron infection in this investigation. Omicron's 2-dose VE against hospitalization was lower than Delta's, although both variants' 3-dose VE against hospitalization was high. After dose 2, protection against Omicron infection began to fade after 3 months, implying that a shorter delay between second and booster doses would be helpful. The immunocompromised population's lack of protection against Omicron infection highlights the need of monitoring the efficacy of the suggested fourth dose (booster) for this population.