To Boost or Not to Boost for COVID-19: How Should We Approach this Question?

COVID-19, which has dominated world attention for over two years now, will continue to be in the forefront of public health for the foreseeable future. With “COVID fatigue” setting in, health authorities are facing a crisis in public confidence. For example, The Centers of Disease Control and Prevention (CDC) recently announced that they are pivoting their language on what it means to be fully vaccinated. If you recently got your second dose of a COVID-19 vaccine and you aren’t yet eligible for a booster shot, you are considered up to date. But, according to Dr. Rochelle Walensky, director for the CDC, if enough time has elapsed since your second shot and you’re eligible for the booster but haven’t gotten it, you would need to get it to be fully up to date. Dr. Anthony Fauci adds, “One of the things that we’re talking about from a purely public health standpoint is how well you are protected, rather than what a definition is to get someone to be required or not required.” This announcement follows on the heels of many cities, such as Washington DC, requiring vaccines to enter restaurants and gyms, with staff demanding that customers show their vaccination cards as proof to comply with this rule. Chicago City Inspectors have cited 13 bars and restaurants and 9 fitness centers for failing to enforce city rules that require all customers to present proof of vaccination. One can legitimately question whether it makes sense for those who have recovered from the virus, especially Omicron, to get further boosters, or if this is a shortcoming of establishing mandates based on vaccination status rather than immune status.

This article will attempt to review and set the record straight on what we know about vaccines in general, the COVID-19 vaccine, and what public health messaging should focus on when any future pandemics arise. The seven topics covered will be: (1) a definition of what vaccines are and how they work; (2) why immunity conferred by some vaccines is more durable than for others; (3) the two major types of immunity: humoral (antibody mediated) and adaptive (mediated by subsets of white blood cells); (4) COVID-19 vaccines and their efficacy; (5) vaccine evasion and breakthrough infections by the Omicron variant; (6) transitioning from a COVID-19 pandemic to an endemic disease; and (7) lessons learned from the COVID-19 pandemic.

Let us begin with the definition of a vaccine and a brief explanation of how vaccines work. According to the World Health Organization (WHO), vaccines trigger your immune system, your body’s natural defenses, to create antibodies to fight infections just as it would do if it were exposed to infectious agents (pathogens) such as bacteria, toxins, or viruses for the first time. The key ingredient in a vaccine can be a killed, or otherwise weakened, whole viral particle or bacterium, individual specific parts (subunits) of the germ, known as antigens, to trigger your immune system, or just the genetic material, DNA or RNA, that provide the blueprints for your own cells to produce specific protein antigen components of the virus or bacterium. Vaccines trigger your immune system to respond as much as it would have if it were exposed to the actual pathogens themselves, but without actually causing the disease itself. The antibodies produced by the vaccine work in several ways to prevent or mitigate infections. They can bind and directly inactivate the pathogens; these types of antibodies are called neutralizing antibodies. Other types of antibodies when bound to the pathogen act as sentinels or flags to recruit other components of your immune system to punch holes in bacterial cells, or to enable your white blood cells to engulf and digest the pathogens in a process known as phagocytosis.

Some vaccines can give you life-long immunity to a pathogen while others need booster doses a few months or years later. For example, tetanus boosters are given every 10 years, the shingles vaccine, Shingrix, requires a second shot 2-6 months after the first dose, and flu shots are given annually. According to Hai Tran, PharmD, the associate director of Pharmacy Services at Cedars-Sinai, the length of vaccine-induced immunity depends on several factors. If the virus replicates quickly, there is a greater chance that more mutations, also known as variants, will arise which makes generating a vaccine a moving target. Viruses that are stable, meaning that they have low mutation rates, offer a big advantage to vaccine makers in that immunity from a vaccine will be durable over time. Examples of highly contagious viruses that were almost eradicated by vaccination alone are smallpox and polio; these have low mutation rates. Measles is also a stable virus that is not likely to replicate and immunity from the vaccine is long-lasting. On the other hand, the influenza virus replicates quickly and mutates frequently and so poses a challenge for vaccine development. Every year there are multiple new strains of the flu virus. This year’s flu shot was quadrivalent, meaning that it was developed to protect against 4 different variants of influenza. Next flu season there will likely be new variants yet again which is why annual flu shots are recommended.

Immunity given by the initial production of antibodies in response to a vaccine or the pathogen itself is known as humoral immunity. However, there is another form of immunity known as adaptive immunity that is mediated by T and B cells which are subsets of your white blood cells. Adaptive immunity functions as an immunologic memory to handle subsequent infections from the same pathogen. Memory T cells remain in circulation from the initial exposure to the vaccine or pathogen. Memory B cells are those which produce the antibodies. Adaptive immunity helps your immune system distinguish foreign, or “non-self” antigens from pathogens from “self” antigens which are components from your own cells which you obviously don’t want your immune system to attack. Ethan Smith, PharmD, Manager for Drug Use Policy at Cedars-Sinai explains, “Counting antibodies doesn't give you a full picture of how well you're protected, because vaccines also train B cells and T cells.” Dr. Smith continues, “When confronted by a known enemy, 'memory' B cells quickly deploy new antibodies to stop infection. When scientists are developing a new vaccine, they do preliminary studies to get an idea of how many doses may be needed. They measure how many antibodies are produced from one shot, and how much more protection you might get from a second dose. If researchers decide that one dose gives enough protection and that a second dose doesn't significantly improve things, they'll develop it as a one-dose vaccine.”

It is important to note at the outset that COVID-19 vaccines cannot and will not make you sick with COVID-19. Any symptoms, such as fever, that you may get after vaccination are not because of the virus. Rather, they are signs that your body is generating an immune response against the virus that causes COVID-19. The virus that causes COVID-19 is a severe respiratory syndrome (SARS)-like coronavirus termed SARS-CoV-2. A virus surface spike protein mediates SARS-CoV-2 entry into cells by binding to its receptor, known as human ACE2. As detailed by Heinz and Stiasny, all current COVID-19 vaccines authorized for general use were developed using the viral spike protein, known as the S protein, of the SARS-CoV-2 virion as their key component to confer immunity by the production of antibodies to the key S protein that allows the attachment and fusion of the SARS-CoV-2 virus particles to cells that line your nose, mouth, and lungs via ACE2 receptors. Thus, these receptors act as a cellular doorway for the virus that causes COVID-19.

Just because antibody levels may disappear after a COVID-19 infection subsides does not mean that your immune system forgets how to combat the virus. The article by Cox and Brokstad, published in Nature Reviews Immunology in August 2020, reports that although antibodies to SARS-CoV-2 are not maintained in circulation following recovery from the virus, their absence does not necessarily mean an absence of immune memory. They write, “Robust immune responses with spike-specific neutralizing antibodies, memory B cells and circulating TFH cells have been found in patients who have recovered from COVID-19 infection,” citing a study by Juno et al.

A critique of the booster policy is that, to date, none of the major COVID-19 vaccine suppliers have altered the original formulations of their vaccines. The contents of your second dose of the COVID-19 vaccine, be it from Pfizer or Moderna, were the same as what you received in the first dose. A COVID-19 booster, which is a third dose of the Pfizer or Moderna vaccines for given at least 5 months after the second dose or a second dose of the J&J vaccine at least 2 months after the initial shot, is also from the manufacturer’s original series; however, only half of the original Moderna dose is recommended as the booster. According to the CDC guidelines, adults over 18 can mix and match their booster shots, with those having received the first 2 doses of either Pfizer or Moderna being able to get boosted with either manufacturer’s vaccine while it is preferred that those who received the J&J vaccine get either the Pfizer or Moderna boosters.

But are these immunizations effective and what are potential limitations to their ability to protect you from COVID-19 infections? Gilbert et al., in an article appearing in the November 23rd 2021 edition of Science, describes the efficacy of the Moderna vaccine to protect from COVID-19 infection by measuring the levels of antibodies a patient produces in their blood serum in response to doses of the vaccine and the ability of those antibodies to neutralize infection. To accomplish the task of screening patient serum samples on a large scale, they built a simulated receptor binding system using a virus-like scaffold expressing the S protein from the SARS-CoV-2 (a spike-pseudovirus), and a genetically engineered cell line overexpressing the ACE2 receptor instead of using the actual SARS-CoV-2 virus and cells from a human respiratory tract. The authors incorporated light-generating components into this system so that when the spike-pseudovirus binds to the ACE2 expressing cells, light is generated. This light, known as chemiluminescence, is then able to be measured and quantified. Antibodies that blocked or neutralized binding of the S protein to the ACE2 receptors significantly reduced the amount of the light produced in the test system as compared to control levels of light generated by binding in the absence of neutralizing antibodies.

The authors conclude that COVID-19 risk decreased incrementally with increasing antibody levels following dosing with the Moderna vaccine. However, they concede that there were limitations to their study, including: the inability to control for SARS-CoV-2 viral exposure levels; a lack of ability to assess spike-specific functional T cell responses which, as mentioned earlier are involved in adaptive immunity; and the inability to assess a booster dose because the study predated the inclusion of a third dose. Most notably the COVID-19 patient serum samples studied were from infections with SARS-CoV-2 viruses that had a spike protein sequence similar to that of the vaccine thus precluding the assessment of vaccine robustness to SARS-CoV-2 variants of concern. In summary, while their findings validated vaccine efficacy by measuring the antibodies produced in response to infection or vaccination, the authors could not establish that these antibodies would provide robust protection against emerging SARS-CoV-2 variants.

The notion that the current crop of vaccines are not as effective against emergent strains is confirmed by a study from Liu et al published in Nature on 23 December 2021 that indeed found that the Omicron variant is markedly resistant to neutralization both by serum from convalescent patients and from individuals vaccinated with the widely used COVID-19 vaccines. Even serum from individuals vaccinated and boosted with the Pfizer and Moderna mRNA-based vaccines had substantially diminished neutralizing activity to Omicron. They conclude that “the Omicron variant presents a serious threat to many existing COVID-19 vaccines and therapies.”

Fortunately, infection by Omicron, which bypasses the immunity conferred by the vaccine, is notably less severe than previous variants. An article by Kuhlmann et al. published in The Lancet on 18 January 2022, documented breakthrough infections with the Omicron variant in seven individuals despite receiving three doses of mRNA vaccines. In these breakthrough cases, illness was either mild or moderate and none required hospitalization. They also noted that Omicron is much more transmissible but less virulent than other strains of SARS-CoV-2; as it infects rapidly but does not yield as severe respiratory symptoms seen in previous variants. Their findings demonstrate “insufficient prevention of symptomatic infection in otherwise healthy individuals who had received three doses of COVID-19 mRNA vaccines … [and] support the need for updated vaccines to provide better protection against symptomatic infection with Omicron.” T cell responses were also detected from these recovering individuals. These cell-mediated responses were not limited to only the spike protein, but also included the nucleocapsid and membrane proteins which are additional components of the SARS-CoV-2 particle. This is an encouraging sign that a broad, adaptive immunity is also developing in response to Omicron infections.

As mentioned earlier, vaccine boosters serve to boost levels of circulating antibodies when immunity from earlier shots wanes. However, if these circulating antibodies are not at all effective, or are less effective, against the Omicron variant as compared to their efficacy with earlier variants, one must question whether it is prudent to keep boosting with the original formulations of the COVID-19 vaccines. Pfizer’s CEO, Albert Bourla, has said that they could be ready to file for approval for a redesigned vaccine to fight Omicron and be able to mass produce it by March 2022. However, he feels that from a public health perspective, an annual vaccine that covers Omicron while not neglecting other variants would be a good solution.

But for an Omicron vaccine to be effective in stemming the current tide of cases, according to Dr. William Moss, executive director of the International Vaccine Access Center at the Johns Hopkins Bloomberg School of Public Health, it would have been needed to be introduced to the general population back in December 2021. Dr. Moss further commented that, “it [developing and mass producing an Omicron vaccine] still could be valuable but I do think in many ways, it’s too late” for the current wave of COVID-19 cases. More than 95% of reported COVID-19 cases were due to the Omicron variant as of early January 2022. If such a vaccine had been available earlier, it “might have been sufficient to prevent some of these illnesses and better protect our workforce, particularly health care workers,” says Moss. But since infection from Omicron spread so rapidly, a targeted vaccine could not be developed in time.

All this information about Omicron bypassing the vaccines and being highly transmissible while causing less severe infections raises the question: Is COVID-19 transitioning from pandemic to endemic? “What an endemic phase of a viral infection means is that it’s not causing the terrible hospitalizations of the pandemic phase but that we’ll have enough immunity of a population so it’s kept down to low levels,” said Dr. Monica Gandhi, an infectious disease doctor at the University of California, San Francisco. She feels that the Omicron variant could be the driver of COVID-19 into endemic status. What would life be like when Omicron is declared an endemic disease? Dr. Ghandi feels that it will be managed more like we manage the flu virus, using vaccines, treatments, and recommending those individuals who are more vulnerable to wear masks inside. “We will likely not be masking, distancing, contact tracing, doing asymptomatic testing,” Dr. Gandhi said. She continues that “There’s [an] incredible number of cases in both vaccinated and unvaccinated. What that does is it exposes you to the entire virus and you develop antibodies, T cells and B cells across the entire virus.” In other words, by recovering from an infection of Omicron, you develop both humoral and adaptive immunity.

Even public health officials like Dr. Fauci are now positing on learning to live with endemic COVID-19. "Control means you're not eliminating it, you're not eradicating it," he explains. "But it gets down to such a low level that it's essentially integrated into the general respiratory infections that we have learned to live with." In other words, just like the flu or the common cold. "If we have those things in place – vaccine testing, masks, therapy – we could keep it at that low level," Fauci said. He confirms that the durability of protection from boosters requires further studies and explains that waning antibody levels are normal. However, Fauci is now invoking that adaptive immunity may also be at work. "But there's an element of the immune response — B cell memory and T cell responses — where, even though you do see a diminution of antibody levels, it is quite conceivable, and I hope it's true, that the third shot boost will give a much greater durability of protection."

So, as physicians and scientists in medical communities across the globe are beginning to talk increasingly more about COVID-19 finally transitioning to endemic status, what are some of the reasonable lessons that we can derive from this pandemic?

I was fortunate enough to study pathogenic microbiology as an undergraduate at Rutgers University in the early 1980’s with Dr. Morris Solotorovsky, of blessed memory, who was an author of “Three Centuries of Microbiology” first published in 1965. Dr. S, as we used to call him, was already a septuagenarian when he was my professor. We used to joke that he was around for all three of those centuries of microbiology. He became especially animated when regaling us about Ignaz Semmelweis, the pioneer of antiseptic procedures, who discovered that instances of childbed fever could be drastically reduced using hand disinfection in obstetrical clinics. Nearly 160 years later, frequent handwashing is at the top of the list to prevent infections.

Dr. David Finegold, may he rest in peace, my professor of microbiology in graduate school at University of Pittsburgh School of Medicine who also wore a large pin on the lapel of his lab coat that said, ‘Wash your hands!’, taught us that droplets from sneezes can travel at speeds approaching 100 mph, with coughs expelling droplets at 50 mph. Dr. Finegold’s motto was to cover coughs and sneezes. This is something else that remains an absolute truth.

And I learned from my immunology professors, Dr. Howard Passmore at Rutgers, and Dr. Christine Milcarek at Pitt, that the very young, the very old, and those with underlying medical conditions or taking immunosuppressants are most vulnerable to infection. Again, this has been borne out by morbidity and mortality in the current pandemic.

My mother, neither a microbiologist nor an immunologist, had her own rule: If you’re sick, stay home! (Her chicken soup wasn’t bad either…) No one needs you feeling miserable with fever, coughing, sneezing, or having frequent diarrhea in school or at work. One of the realizations arising from life during the pandemic is that there is an increased ability to work from home for certain types of jobs. Students have also gotten used to remote learning during the pandemic. If you’re sick and shouldn’t be present to potentially infect coworkers, clients, or customers but are still able to muddle through the work or school day, hopefully your employer or school will continue to be able to support remote work or schooling in your home. For those employees who must be physically present at their workplace, employers should be mandated to provide ample fully paid leave as needed for workers when either they or a dependent are duly documented to be sick so that the spread of germs is limited. This is one law that should garner bipartisan support in both houses of Congress!

While Operation Warp speed was extraordinarily successful in bringing about a brand new modality of mRNA vaccines to prevent severe cases of COVID-19 arising from the initial variants, rapidly mutating viruses can outpace this protection. Additional effort must be made to develop rapid tests to further discern the ability of antibodies generated in response to first generation vaccines to neutralize emerging variants.

It is clear that you can’t have a single pronged “vaccine only” approach: parallel paths must also be taken at the same time to develop new types of therapeutics or screen old drugs to find promising leads for further development and make them widely available to those who do get infected. Be prepared for the next pandemic: devote resources to making sure ample supplies of hospital equipment, personal protective gear for front line workers, and tried and true standard operating procedures are in place for manufacturing in our own country to ramp up testing, vaccinations, and therapies, and medical supplies as needed.

Finally, educate the public more effectively on basic principles of immunology and epidemiology in laymen’s terms so they can grasp this information to make more informed decisions about their own health without the need for harsh proclamations or condescension. Individuals must be able to rely upon the relationships that they have with their own trusted healthcare providers for advice that’s tailored perfectly to their own situation.

*About the author: Dr. Keren Hulkower earned a BS in Biology from Cook College, Rutgers University, an MS in Microbiology and a PhD in Biochemistry from the University of Pittsburgh School of Medicine. He held senior research positions in drug discovery and medical assay development at several major pharmaceutical companies before venturing into the world of biotechnology start-ups. Dr. Hulkower currently works as a senior manager for a major non-profit medical organization. He is the author of more than 30 peer-reviewed scientific manuscripts and dozens of abstracts over the course of his career. Dr. Hulkower is also the author of 2 medical fiction novels, Mirror Images and Broken Records. The views, thoughts, and opinions expressed in this article are solely those of Dr. Hulkower and do not reflect those of his employer or this website.