BY AKIKO IWASAKI AND ALBERT KO

Iwasaki is the Sterling Professor of Immunobiology and Professor of Dermatology and of Molecular, Cellular, and Developmental Biology and of Epidemiology at Yale University School of Medicine

Ko is the Raj and Indra Nooyi Professor of Public Health and Professor of Epidemiology (Microbial Diseases) and of Medicine (Infectious Diseases) at Yale University School of Medicine

Several highly effective vaccines were developed at an unprecedented speed to combat the COVID-19 pandemic. During the phase 3 clinical trials, mRNA vaccines had vaccine efficacy of 9495% in preventing symptomatic infections. After the rollout, real-world evidence showed that the mRNA vaccines provided ~90% effectiveness against infection. Then came the variants. The wave after wave of new variants, with ever-increasing transmissibility and capacity to escape existing immunity, challenge the ability of vaccines to prevent infection and transmission. The effectiveness of a primary series of mRNA vaccines (two doses) to prevent hospitalization and death is also being chipped away by these highly immune-evasive variants. Vaccine-mediated protection became shorter-lived, especially with the emergence of Omicron variants. People look at these data and wonder, what is the point of getting the vaccines if they will not prevent symptomatic infections, and the protection does not last? Well, to expect robust protection from just the primary series of any vaccines is unreasonable—and was always likely to be—but somehow society has placed too high a bar on what is considered an acceptable number of doses for COVID-19 vaccines. Instead, we need to understand that we’re going to be getting boosters in the foreseeable future, and to appreciate their benefits.

Vaccines against other infectious diseases are given in multiple doses. Many of our childhood vaccines require multiple doses—5 doses for (diphtheria/tetanus/pertussis), 4 doses (Haemophilus influenza type b, pneumococcal conjugate, inactivated poliovirus), or 3 doses (hepatitis B) are all commonly given before the age of 18 years. These doses are required and not considered optional to achieve immunity. In adulthood, many of these vaccines need periodic booster doses to maintain immunity. The influenza virus requires annual vaccination doses for all ages. Yet, people don’t complain about having to get their 60th dose of the influenza vaccine. We should think of COVID-19 vaccines the same way.

Why do we need booster doses? The primary series of vaccines kick-starts the immune response by engaging lymphocytes, white blood cells that detect specific features of the pathogen to expand in numbers and become instructed to eliminate the pathogen. Most of these cells disappear over time, except for a small subset of cells that are kept by the body for future use. These “memory cells” are responsible for long-lasting immunity against a given pathogen. What boosters do is stimulate these memory lymphocytes to quickly expand in numbers and to produce even more effective defenders. The booster also selects for B cells that can secrete antibodies that are even better at binding and blocking virus infection and spread.

The primary series can be thought of as the high school for lymphocytes, where naïve cells receive basic instructions to learn about the pathogen. Boosters are like a college where lymphocytes are further educated to become more skilled and mature, to fight off future infections. Periodically, these college graduates need refreshers by more booster doses given later in life. This is the case for all vaccines. Booster doses provide the immune system the education it needs to prevent severe diseases from infections.

COVID-19 vaccines also need booster doses for the same reasons. We need to educate, maintain, and improve T and B cell responses to prevent severe disease. Boosters provide significant benefits to people who received the primary series in preventing hospitalization and death. In the U.S. in April 2022, people older than 50 years of age who received no vaccine, primary series only (no booster dose), or one booster dose had 38 x, 6 x, or a 4 x higher risk, respectively, of dying from COVID-19 compared to those with two or more booster doses. During the Omicron-predominant period, the booster dose provided protection from hospitalization even in previously infected people, whether older (>65 years of age) or younger (<65 years of age). Among children and adolescents, a primary series (two doses) of vaccination was less effective in preventing COVID-19-associated emergency department and urgent care encounters during the Omicron wave compared to the Delta period. Immunity also decreases with time since primary vaccination. No significant protection was detected more than five months after a 2nd vaccine dose among adolescents aged 16–17 years. However, a third booster dose restored vaccine effectiveness to 81% in this age group. There is thus a clear benefit of a booster dose across a broad range of age groups studied to date.

Can booster vaccination be improved in the future? Absolutely. We need improved boosters that can provide more durable protection, are effective against variants we encounter moving forward, and do a better job of preventing infection and blocking transmission. For example, booster-induced immune protection wanes within 4-6 months during the current Omicron period. We need vaccine strategies that provide more durable protection. Boosters are now being developed to match the circulating Omicron variant BA.5, which should provide better protection than boosters based on the original strain. However, because of the rapidly mutating nature of SARS-CoV-2, going forward, we will need boosters that can provide coverage against not just the existing but future variants of concern.

Boosters that work against a wide range of SARS-CoV-2 variants, now or in the future, as well as against other coronaviruses that may cause future pandemics need to be pursued. Coronaviruses have made the jump from animals to humans multiple times in history which resulted in pandemics. Vaccines that can broadly protect against a wide range of coronaviruses will also prevent future pandemics. In addition, future boosters should be given as nasal spray vaccines to provide local mucosal immune protection, capable of reducing infection and transmission at the portal of entry for the virus, and reducing long COVID risk. Ultimately, we need booster strategies that can be more easily implemented worldwide and have higher acceptance and uptake rates to provide much-needed immune protection for everyone. An over-the-counter nasal spray booster can bring us closer to that goal.

Researchers and industry are furiously working on developing next-generation vaccines as they did with our current vaccines, which have saved more than 14 million lives during the pandemic. But for now, take the booster doses you are eligible to keep your immune system educated and up to date so it has the best chance of protecting you from COVID-19 in the upcoming winter season and so we can prevent the enormous loss of life we experienced last winter with more than 300,000 people dying in the U.S. from a disease that can be prevented by current boosters.

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