In mid-August, the Food and Drug Administration amended the emergency use authorizations for Pfizer and Moderna to allow a third dose of their COVID-19 vaccines for certain immunocompromised people
The CDC now recommends a booster for those who received the Pfizer vaccine > 6 months ago and meet the following criteria:
- 65 years and older
- Age 18+ who live in long-term care settings
- Age 18+ who have underlying medical conditions
- Age 18+ who work in high-risk settings
- Age 18+ who live in high-risk setting
Note: Regardless of booster status, the CDC still considers any individual “fully vaccinated” after 2 weeks of completing the primary 2 doses.
At the time of this recommendation, there have been over 42 million cases of documented COVID-19 infections resulting in 700,000 deaths in just the United States. Roughly 55% of the population has received either 2 doses of either mRNA vaccine or the single dose J&J vaccine.
So, what’s the deal? Does this mean the vaccines aren’t working?
Israeli data through July of 2021 raised some serious efficacy concerns for those who received the Pfizer vaccine > 6 months ago. Remember, the initial goal of vaccine effectiveness was 50%. While that may seem like a low bar, this would still be more effective than the flu shot.
This bar chart summarizes the frequently referenced Israel data published in July. Essentially, the two columns on the right show that two doses of the Pfizer vaccine offered substantial protection against hospitalization and severe infection regardless of when people were vaccinated. The light blue bar is those that were vaccinated back in January. While severe illness and hospitalization prevention was still high at six months, the protection against developing symptomatic infection was only 16% when the Delta variant took over as the predominant variant.
Since the Israel data came out in late July, the US has done a few studies. The Mayo Clinic published the following effectiveness rates. At first glance of this data, you see that in July, the effectiveness of the Pfizer vaccine decreased to 42% against developing mild symptoms and 75% against hospitalization. While this makes it look like the vaccine may not be effective against Delta. However, they did not correct for the timing of vaccine administration.
A Pfizer-funded study published October 4th, including over 4 million people vaccinated in the US, suggests the decrease in effectiveness likely has more to do with time since vaccination and less to do with the specific variant. This decline was also seen with other variants. Another important takehome from this study is that regardless of the decrease in effectiveness against symptomatic infection, there remains high protection against hospitalization in vaccinated individuals.
This data is summarized in the graph showing effectiveness against infection (top chart) vs. effectiveness against hospitalization (bottom graph). This research indicates that vaccine efficacy began to decline at a constant rate prior to Delta variant emergence in the US, while protection against hospitalization was maintained.
Source: Tartof, et al.
This trend in a decrease in vaccine efficacy against infection with sustained protection against hospitalization and death has been reproduced several times over. The September briefing from the CDC offers an excellent visual summary of these earlier studies.
With over 182 million people fully vaccinated in the US, hospitalization rates are 10-22 TIMES higher in those who are unvaccinated ass compared to vaccinated adults.
So, does the booster offer increased protection?
Israel authorized a 3rd dose of the Pfizer vaccine on July 12 for immunocompromised adults and on July 30 for all adults > 60 years. This was expanded to include all people > 12 years old by the end of August. The caveat is that people had to be at least five months past their 2nd dose to qualify for a booster.
Both studies were rather large, extracting data from the Israeli Ministry of Health database. Both compared people who received a booster dose to those who completed the 2-dose Pfizer series at least five months prior. Unvaccinated patients were not assessed in these studies.
Results of these studies showed that vaccine effectiveness against delta after a booster dose returned to effectiveness levels seen following the 2nd vaccine dose against alpha.
If VE after waning is 50% for INFECTION and increases 10-fold it becomes 95%
If VE after waning is 80% for SEVERE and increases 10-fold it becomes > 97%
A summary of outcomes is listed in the table below.
From this data, it is reasonably apparent that a booster offers increased odds of protection compared to those who have not received a booster. However, both studies are limited in the short follow-up periods, with a maximum of 21 days for documented infection and 16 days for severe disease. It is also important to note that the Patalon et al. study is pre-print and not yet peer-reviewed.
A report from the Israeli Ministry of Health offers a closer look into these benefits. The reproduction number (R0) right before the decision to provide boosters was relatively high, at 1.33, doubling every ten days. Remember from previous posts; if the R0 is > 1, the disease will continue to spread through a community. Our goal is to drive this number below 1.
Source: FDA
Following the booster initiative, this was effectively achieved.
Source: FDA
In a projection model from the Israeli Ministry of Health, delay of just 2 weeks in initiating their booster vaccination program could have led to significant increases in hospitalization and easily exceeded the national capacity.
Keep in mind that vaccines mean more than just personal protection when it comes to public health. It should be obvious to understand that if fewer people get sick, the transmission will also decrease. Data published this week shows that individuals who receive two COVID-19 vaccine doses and later contract the Delta variant are less likely to infect their close contacts than are unvaccinated people. However, this benefit was only seen within the first three months following vaccination.
According to the CDC, the number needed to vaccinate to prevent one hospitalization over six months is summarized below. It is essential to consider that this data is just for the rate of hospitalizations from a booster dose. As discussed in prior posts, disease not requiring hospitalization can still carry significant morbidity, with up to 50% of mild cases having long-hauler symptoms.
The largest benefit from booster vaccination is individuals > 65 years of age. The benefit to other ages is incrementally smaller, given higher vaccine efficacy maintained from the primary series at this time. This will likely change as we know vaccine efficacy decreases over time, regardless of age.
Source: CDC: Vaccine effectiveness against symptomatic infection, by age and time since vaccination.
So, are the boosters safe?
The short answer is, they appear to be just as safe as the first two doses. Before the Israeli Ministry of Health briefing on September 17th, 2.8 million booster doses had been given. While under-reporting is expected, ALL hospitalized and deceased patients were independently investigated.
From these 2.8 million doses, we have the following data:
There were 1,328 reports of non-serious adverse events that were like those seen in from the first 2 doses.
Source: FDA
There were 19 serious events reported
Source: FDA
Overall, the immediate safety events from the booster vaccine appear like those seen from the first and second doses. This data is just for the Pfizer vaccine. While rare clotting disorders have been described with the AstraZeneca and Johnson & Johnson vaccines, these have not been associated with the mRNA vaccines. There has been an association with a small increased risk of Myocarditis from the Pfizer vaccine, almost all events occurring in young males. The following infographic was put out by the CDC to address this concern.
Bottom Line:
- 3-fold reduction in symptomatic infection
- 5-fold reduction in severe illness
- Post-booster efficacy against delta is similar to pre-waning efficacy against alpha
- Adverse events appear similar to those seen in the first and second dose
Should those who have had COVID-19 get a booster?
Let’s summarize what we know about prior infection and the vaccines….
In a peer-reviewed study published in June, researchers showed that the antibodies from the vaccine more targeted to the receptor-binding domain of the SARS-CoV-2 spike protein than antibodies elicited by natural infection and had greater binding breadth. This suggests that vaccine-induced immunity was more equipped to handle mutations in this region than those from natural disease.
In another peer-reviewed study from June published in Nature, researchers showed that the Pfizer vaccine produced more neutralizing antibodies than unvaccinated individuals who recovered from COVID-19 but did not require hospitalization.
One month later, a pre-print study of patients who recovered from severe SARS-CoV-2 infection, showed infection produces B-cell responses that continue to evolve for at least one year. During that time, memory B-cells express increasingly broad and potent antibodies that were resistant to mutations found in the current variants of concern. When compared to SARS-CoV-2 naïve patients vaccinated with either mRNA vaccine, natural infection produced antibodies with greater potency and breadth when compared to antibodies obtained from vaccination alone, suggesting those vaccinated following illness will have heightened immune protection.
A study from the Cleveland Clinic tracked cases in healthcare workers who were either vaccinated or previously had COVID-19. They found that the rate of reinfection is essentially the same between the two groups. Another study out of Qatar similarly found that the chance of reinfection is low among those who previously had COVID-19 and those who were vaccinated.
Then, on August 13th, the CDC released a study comparing the effectiveness of COVID-19 vaccines versus natural immunity from prior SARS-CoV-2 infection. In this study, being unvaccinated was associated with 2.34 times the odds of reinfection compared with being fully vaccinated. A concurrent study showed the Pfizer and Moderna vaccines prevented 96% of hospitalizations, and the Johnson & Johnson vaccine prevented 84% of hospitalizations in adults aged 65-74 years old.
It is important to note that these studies took place before the Delta variant showed up in the United States. Newer data shows antibody response from natural infection is likely similarly suppressed as is seen with the vaccines.
In a peer-reviewed publication from June, research showed that antibody levels obtained after a mild natural infection were similar to getting a single dose of either mRNA vaccine. This suggests that a natural infection essentially serves as the “first dose” of a two-dose vaccine.
Another study in JAMA showed that, compared with unvaccinated participants, those who had received at least ONE dose had higher antibodies and a nearly 50-fold increase in neutralizing activity.
Conslusion
We all knew boosters would eventually be recommended. However, we need to stop considering booster recommendations as a sign of vaccine failure. It certainly is not. The immune system is quite complex. Antibody levels and the humoral immune response are only one part of the equation. Cell-mediated immunity likely plays a significant role, as is made apparent by the sustained benefit of the vaccine at preventing hospitalization and death well past six months. It is quite possible that a booster could provide a more extended and more sustained humoral response, as is seen with other vaccines. The verdict is still out on that, of course.
The booster offers further benefits to public health initiatives. Boosters seemingly decrease transmission as they restore protection to the delta variant close to those seen when the alpha variant was prevalent and have reduced the R0 below 1 in Israel following the initiation of their booster campaign.
Not receiving the booster does not that you are not “fully vaccinated” by the current CDC definition. If you are interested in enhanced personal protection (11-fold increase in efficacy against symptoms) and contribution to the public health campaign, the booster is likely right for you. The safety profile appears no different than that seen in the primary series.
- Monoclonal Antibodies for COVID-19 – An evidence based update - January 18, 2022
- COVID-19 Vaccines in Pregnancy - January 6, 2022
- COVID-19 Boosters….are they necessary? - October 8, 2021