When Experts defy the Officials, who are telling the truth?
- Timing
The CDC stated that adults who completed their primary vaccine series are eligible for the updated booster if it’s been at least two months since their previous vaccine. They advised those who recently had an infection to wait three months before getting boosted.
Is such a short interval optimal if the goal is to have robust fall/winter-long protection?
Let’s look at some immunological studies.
An earlier study showed that a longer period between doses could generate a higher antibody response, amplified T cells, and enriched memory B cells.
More recent studies during the Omicron variant dominating period continue to show the benefit of waiting for a longer period between doses to increase both neutralizing antibodies and memory B cells.
A study published in late August 2022 by a research group from Singapore analyzed the vaccine effectiveness outcomes of over two million of its residents aged 30 years or more. They reported that the estimated booster effectiveness against Omicron infection waned from -2.8% to 14.6% after five months. However, against severe COVID-19, the estimated booster effectiveness was 87.4% 15 to 60 days after boosting and 87.2% 5 to 6 months after boosting. (https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2795654)
A different study done by a group from the University of Pennsylvania showed that in relatively younger people, both with and without previous infection, neutralizing antibody titers stabilize about six months after primary vaccination, and memory B cells stable for more than nine months after vaccination and with more than 50% cross-binding activity against Omicron. (https://www.cell.com/action/showPdf?pii=S0092-8674%2822%2900456-1)
T cells immunity, or the immunity against severe illness from COVID vaccines, is still holding up, and it is evident by the lack of high hospitalization levels even with BA.5 becoming dominant this summer. (https://www.science.org/doi/10.1126/science.add2897)
Someone may say, I just want a high level of antibodies, so I will get a booster as soon as possible. What’s wrong with that?
The same study from UPenn also pointed out that the greatest increase in antibody response from a booster is when the pre-boost antibody level is low. When a person still has a high level of circulating antibodies from a recent booster or infection, a premature booster may even be detrimental. A pre-print study done by the National Institute of Health showed that giving a booster two months after a recent infection does away with effective B cell responses. (https://www.medrxiv.org/content/10.1101/2022.08.30.22279344v1.full.pdf)
CDC’s 3-month post-infection booster recommendation makes some sense, but it depends on people’s awareness of COVID infection.
So, do most of us know we have been infected?
A recent study in JAMA showed that 56% of people infected with the Omicron variant were unaware of the infection. (https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2795246)
A recent study from Portugal showed that a previous BA.1/2 infection provides upwards of 75.3% protection against re-infection with BA.5. (https://www.nejm.org/doi/full/10.1056/NEJMc2209479)
All of these data means the population already has high immunity against severe disease. If the Fall booster is to prolong infection protection, then the CDC’s message to tell people to wait at least two months after the previous vaccine is not supported by data but is also very confusing for people who are considering the new bivalent booster for the most optimal personal protection.
In contrast, the Canadian National Advisory Committee on Immunization recommended that the updated bivalent vaccine be offered six months after previous vaccination or infection. (https://www.canada.ca/content/dam/phac-aspc/documents/services/immunization/national-advisory-committee-on-immunization-naci/naci-summary-september-1-2022.pdf)
- Long COVID
One of the persuasive points to get more boosters is to reduce long COVID. An Italian study published in JAMA showed the prevalence of long COVID was 41.8% in unvaccinated patients, 30% with one dose, 17.4% with two doses, and 16% with three doses. Although we see a progressive decrease in long COVID incidence with each dose, the additional benefit for long COVID from the third was only 1.4% better. If this pattern holds, then any additional doses may have an even smaller benefit in preventing long COVID.
The study also pointed out the risk factors for long COVID, such as older age, higher body mass index, allergies, and obstructive lung disease. (https://jamanetwork.com/journals/jama/fullarticle/2794072)
- Transmission
Dr. Jha implies that getting the new booster by Halloween will reduce the risk of transmitting COVID to older adults at home. Is that a fantasy or reasonable?
Dr. Paul Offit was asked a similar question recently during an online interview, and let’s look at what he said.
(Paul Offit)
Clearly, vaccine experts like Dr. Offit do not believe it is reasonable to have a goal to prevent transmission or mild disease, at least with the current vaccine. The main reason is that COVID has such a short period of incubation time. Unless the neutralizing antibody level is constantly topped off, it is not possible to prevent all mild diseases and transmission. A recent systematic review and meta-analysis reviewed 141 articles and concluded that the average incubation period of COVID-19 caused by the Alpha, Beta, Delta, and Omicron variants were 5.00, 4.50, 4.41, and 3.42 days, respectively.
(https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2795489)
That puts the Omicron incubation period on the spectrum of flu and the common cold.
Someone can argue that there are studies showing reduced transmission in households.
A study done in the Alpha and Delta variant era showed reduced household transmission in Israel. (https://www.science.org/doi/10.1126/science.abl4292)
An updated systematic review and meta-analysis suggested household secondary attack rates are as high as 42.7% for Omicron BA.1.
(https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2791601)
- Knowledge Gaps
There are several significant knowledge gaps in the current bivalent vaccine.
- Does bivalent vaccine increase spike-specific T cell immunity? No vaccine manufacturers provided that information.
- Why are other antigens or immunogens, such as the nucleocapsid, membrane proteins, or other conserved regions, not considered in a booster vaccine to broaden cellular immunity?
If you were my student and had taken my immunology course, you would have completed an assignment brainstorming new antigens for a booster vaccine. I am surprised that the two big mRNA vaccine manufacturers are still not moving in that direction.
- Will the updated booster vaccine improve clinical efficacy?
The manufacturers present human clinical data showing the BA.1 bivalent vaccine booster had less than twofold higher BA.1 neutralizing antibodies than the original booster. But does that translate to clinical efficacy?
We have seen that story before. The Moderna mRNA vaccine generated twice as many antibodies as the Pfizer mRNA vaccine. (https://jamanetwork.com/journals/jama/fullarticle/2783797)
But the initial clinical trial data showed very similar efficacy in preventing COVID (95% vs. 94%). This indicates that higher antibody levels may not have meaningful clinical differences.
