Vaccine Effectiveness In The Omicron Wave

As everyone knows, the SARS-CoV-2 Omicron variant began to emerge late last fall, just in time for traditional winter holidays.

The US Omicron wave peaked in mid-January at around 800,000 new cases per day — more than three times higher than the previously largest peak (around 240,000 cases per day), which occurred almost exactly one year earlier.

Scientists knew from the beginning that Omicron was different. Virologists quickly discovered that the variant possesses thirty-two mutations in the gene that codes for the Spike protein, a key part of what makes the SARS-CoV-2 virus recognizable by people who have immunity, suggesting that Omicron might be a so-called “escape mutant”, i.e. a variant of the virus so different from the ones that came before that it is not recognized by the adaptive immune system. Of course, escape comes in degrees and the protection offered by vaccines varies accordingly. For a “fully” escaped mutant, vaccines would not provide any protection at all.

Immune escape is not the only reason why vaccines lose their effectiveness. Immune waning occurs when an individual’s immune response diminishes over time. It is well known that neutralizing antibodies to SARS-CoV-2 begin declining in a matter of weeks after vaccination. Less well known is that the more durable B-Cell and T-Cell responses also decline over time. Taken together, these three weapons of the immune system lose their collective effectiveness over time.

So, how much did these two factors — immune escape and waning immunity — contribute to the massive Omicron wave?

The best way we have to look at this is at studies of Vaccine Effectiveness (VE), which seek to measure the actual real-world benefits of a Covid-19 vaccine. Results are now starting to roll in.

Two studies in the CDC’s Morbidity and Mortality Weekly Report are in general agreement that the protection offered by vaccines, particularly the mRNA vaccines developed by Moderna and Pfizer, remained pretty strong until Omicron started taking over. The caveats are that protection was much greater for those who were boosted than for those who received just two doses, and, now that we’re battling Omicron, vaccines are primarily a weapon against severe disease and death, not transmission.

Let’s take a closer look at the numbers.

Study 1

The first study was a “test-negative” design. A network of eight care providers operating out of 383 emergency departments and urgent care clinics and 259 hospitals looked at the vaccination status of adults seeking treatment for Covid-19 compared with those seeking treatment for other conditions.

They divided their study period into two intervals based on the relative frequency of variants in the region:  an initial period of “Delta predominance” followed by a shorter period of “Omicron predominance” (although it’s probably better to think of this later period as “Omicron emergence”, as December cases were really a mix of Delta and Omicron variants). The test-negative design allowed them to estimate the effectiveness of different vaccine dosing regimens compared with a baseline of patients who had not been vaccinated at all.

During the Delta predominant phase, vaccination with two doses of an mRNA vaccine was 86% effective against illness severe enough to warrant care-seeking as long as the most recent dose was no earlier than 179 days earlier.

Effectiveness dropped to 76% for those who had had their second dose 180 days earlier or more. It’s important to understand that nothing magical happens at day 180, and the actual waning of immunity is a gradual process. But, studies like this need to group people into bins for statistical purposes.

Encouragingly, however, effectiveness jumped to 94% for those who had received a booster.

For comparison, during Omicron predominance the comparable figures were 52%, 38%, and 82%.

Study 2

A second study looked at vaccination effectiveness over a longer study period, from April 4 to December 25, 2021, meaning that vaccine effectiveness could also be compared to a pre-Delta baseline. Another difference is that people who had been vaccinated with the Janssen (Johnson & Johnson) vaccine were also included.

This study measured Incidence Rate Ratios (IRRs) and compared case rates and death rates between unvaccinated and fully vaccinated adults. An IRR is the relative hazard faced by an unvaccinated person compared with a vaccinated person. A measure of vaccine effectiveness that can be compared to the previous study can be calculated from IRR using the formula VE = 1-(1/IRR).

The first piece of information added by the new study concerns how effective vaccines were in the pre-Delta period, defined in this study as April-May 2021.

The difference between the pre-Delta period (blue) and the Delta predominant period (yellow) is about 12.4%. It is likely that this is largely due to waning immunity. For comparison, the difference between the Delta predominant period (yellow) and the period of Omicron emergence (green) is another 12.7%. 

The context

When looking at these patterns, it’s important to keep in mind that even though Omicron was emerging during December, it didn’t dominate until more recently. The results of both studies should be considered in the context of the overall state of the epidemic in the US at the time the studies were conducted. The following figure from nextstrain.org suggests that Omicron represented only about 20% of Covid-19 cases in North America in December and even now is only about three quarters of cases. 

This agrees with data from the CDC for December, but not for January, during which time CDC data show Omicron strongly dominating.

This means that overall vaccine effectiveness to protect against severe Covid-19 symptoms during the period when Omicron emerged is not the same thing as effectiveness against Omicron.

An even more recent study (that has not yet been peer-reviewed) was specifically designed to measure vaccine effectiveness against Omicron. This study found that a full two-dose course of mRNA vaccines failed to provide any measurable protection against infection with Omicron and that boosting with a third dose of an mRNA vaccine increased effectiveness against transmission back up to only 37%.

Additional data from Study 2 are roughly consistent with this conclusion, showing a significant difference between vaccine effectiveness in people with two doses compared to those with a booster, and statistically negligible differences among the three main vaccines.

None of this is to imply that the vaccines are unimportant in the ongoing fight to mitigate the damage of Covid-19. Even two doses of an mRNA vaccine provide significant protection against hospitalization. What it does point to is the impossibility of vaccinating our way from the current state to Zero-Covid, an objective that has long been out of reach in the US anyway.