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Journal Club: The 4th Shot

Falatko, J.


The CDC issued a statement a couple of months ago recommending a 4th covid booster to all individuals over 50 if it has been 5 months since your 1st booster. Since this statement the 4th shot has been the #1 FAQ I’ve had in the office. My practice consists of mainly patients over 50, but I have many patients, friends, and family that are around individuals over 50 on a regular basis that are also wondering if they should get another booster. The most common follow-up question is…Do I really need this?


It's clear that many people have gone way past covid fatigue and are now getting vaccine fatigue. The CDC based their recommendation on observational data out of Israel, which authorized a 2nd booster in early January for high-risk individuals. The study compared infection rates in three different groups. Group 1: 3-dose recipients, Group 2: 4-(2nd booster) dose recipients, and Group 3 (internal control): received 4th dose within 3-7 days. The internal control was used to reduce residual confounding based on the assumption that those seeking a 4th dose may represent a risk adverse cohort that is dissimilar to the general population.


They excluded patients that had been infected before the start of the study period. Anyone that received a 4th dose before January 3rd, and anyone that received their third dose before July 30th, of 2021. The Pfizer vaccine was the only vaccine studied. The endpoint was infection rates based on 100,000 person days at risk.


Roughly 625,000 people were identified in the national database for the 3 dose and 4 dose groups.


The 3-dose group have 31 million at-risk-days compared to 23.9 million at-risk-days in the 4-dose group. They had to adjust their result to account for this increased exposure risk.


There were 111,780 confirmed infections in the 3-dose group compared to 42,325 in the four-dose group


The adjusted confirmed infection rates:


4-dose group: 171 per 100,000 person days

3-dose group: 308 per 100,000 person days


There were 1210 severe infections in the 3-dose group compared to 355 in the 4-dose group. This is a rate of 0.19% and 0.05% respectively. An absolute risk reduction of 0.14% which equals a number needed to boost of 714 to prevent 1 severe infection.


Here is a very poor example of the data displayed graphically that (IMO) over-exaggerates the effect size:





Here’s the quick summary: The 4-dose group did have their infection rate cut in half. There was a 4-fold reduction in severe infection rates 4 weeks after the 4th dose. The effect began to weaken at 8 weeks. The base rate for COVID infection in Israel at the time was quite high. Severe infection rates were very low in both groups. They didn’t report on deaths, but one can assume they were much lower than the severe infection rate.


You may be asking yourself…How can this be? How did 1 in 6 people in the 3-dose group get infected. Well, 94% Israel’s population lives in urban areas. People living closer together tend to spread infectious diseases much easier. Obviously, the US is not Israel. The U.S. has about 1/4 the population density of Israel with roughly 80% living in urban areas.


Current infection rate in the U.S. is around 76 per 100,000 people. About 80% of Americans have received at least 1 dose of the Covid vaccine. The prevalence of COVID in Israel at the time of this study was likely much higher than current conditions in the US.


Figure 2: Current U.S. Covid-19 cases.






The seasonal trends are quite visible. Recall in October of 2020 testing was only available at a physicians office or testing center. The true counts were likely much higher. Why now? Why recommend a 2nd booster when case counts are low, and we are close to the summer months? Is this the right strategy?


The vaccine became available in January of 2020, and most individuals were boosted in late October early November of 2021. Today is May 10th, 2022, 6-7 months after the 1st booster campaign.


It’s difficult to know if the CDC is strongly pushing for a 2nd booster or if they just wanted Americans to have the option. The data from Israel is not strong for the prevention of severe infection and death. Not to mention it is difficult to extrapolate to America. After the press release there hasn’t been much emphasis placed on the 2nd booster. Which makes me believe they just wanted Americans to have the choice.


In my opinion, the strategy may be seriously flawed. This is based on the half-life of neutralizing antibodies and the current season we are about the enter. The typical IgG antibody against covid floats around at high titer in a vaccine recipients’ blood for roughly 9-12 months. This is typical for most IgG antibodies after infection or vaccination.


Figure 3: Direct your attention to the graph in the top right corner.





When someone with circulating neutralizing antibodies receives a vaccine designed to boost those same antibodies, the vaccine is quickly bound up by said circulating antibodies. This effectively weakens the dose resulting in a dampened response.


In this scenario, there is small amount of freshly produced antibodies. The titer drops sooner than expected because most of the float is antibodies from the previous booster. This phenomenon was observed in this study, as well as other previous trials investigating boosters. In this paper, the effectiveness of the 4th shot began to wane at 8 weeks. The neutralizing antibodies from the previous vaccine must be gone to get the desired response. Because the antibodies floating around were old and ready to be recycled. That’ doesn’t mean there is no immunity, there is just a lack of protection against acquiring and circulating covid.


This sets up the potentially dangerous scenario if many patients get boosted this spring. In the spring and summer months you can expect case counts to remain low because transmission outdoors is far less likely than indoor crowded spaces. Fall and winter set in. They get another booster this fall, but the response is dampened again, setting us up for a large amount of virus in the population in the middle of winter.


Most of the general public has been taught that immunity from the vaccine lasts anywhere form 6-9 months. In the scenario I describe above the immunity window will deviate significantly between individuals based on the timing of the previous booster.


Timing of boosters needs to be thoughtful. Your immune system needs high exposure to something it believes to be a threat to mount the appropriate response. If your white blood cells never see the threat, they won’t make fresh antibodies.


I’m not sure why the CDC decided to make this recommendation and then go AWOL for several weeks. I speculate they just wanted to give patients and doctors the choice. The entire department has struggled to be decisive and have lacked transparency for several months now. It feels like they just wanted to "pass the buck". There may be overly cautious for the institutionalized elderly within our population and they didn’t want to be exclusive. Either way, I found the recommendation to be misguided. It lacks a fundamental understanding of immunity and endemic control. I hope I’m wrong.


For the average patient it makes sense to wait until the fall. Your response to the first booster will be cleared and you can get the full effect of the vaccine. My opinion is just one opinion. I encourage everyone to read different points of view. Links to the NEJM paper and the CDC website are below. If COVID has taught us anything it may be that science is more of a collection of opinions based on available data than always fact. And the consensus of those opinions is probably closer to the truth than one study claiming to be fact. Remain open minded and do what is best for you.


CDC Booster: https://www.cdc.gov/coronavirus/2019-ncov/vaccines/booster-shot.html?s_cid=11709:cdc%20covid%20booster:sem.ga:p:RG:GM:gen:PTN.Grants:FY22


NEJM Article: https://www.nejm.org/doi/full/10.1056/NEJMoa2201570

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