Why Vaccine Doses Are Staggered

August 16, 2021

With the growing availability of COVID-19 vaccines, many Americans have had access to a second dose, which is highly recommended for both the Moderna and Pfizer vaccines. Yet some may have difficulty understanding why a second dose is even necessary in the first place, especially when other vaccines – such as the flu shot or the Johnson & Johnson COVID-19 vaccine – do not require a second dose. In order to understand why vaccine doses are staggered, one must first understand the mechanisms underlying active immunity and mRNA vaccines.

Perhaps the most important factor to understand when it comes to vaccine doses being staggered is that, in order for a vaccine to work, it must generate an immune response strong enough for the body to recognize the invader if it was encountered again. One of the key difficulties facing vaccine development is striking the balance between generating a sufficient immune response without actually introducing a harmful pathogen. For this reason, there are a number of different types of vaccine formulations used. In the past few decades, vaccines have typically contained either viral surface proteins, small amounts of virally-produced toxins, or weakened/killed microbes. Each of these approaches has unique strengths and weaknesses in terms of immune response, adverse symptoms, and risk of pathogenesis.

Unlike traditional vaccines, the Pfizer and the Moderna COVID-19 vaccines were formulated using an mRNA design. Although FDA (emergency) approval for an mRNA vaccine was first given in December of 2020, mRNA vaccines have been a topic of research for decades.1 There are many advantages to mRNA vaccines: for example, they can mimic natural viral infections and produce complex multimeric antigens.2 Notably, mRNA vaccines can also be developed fairly rapidly without the need for time-consuming processes, such as fermentation or production via cell culture.

Despite these strengths, a single dose of current mRNA vaccines is typically not strong enough to produce an adequate number of the antibodies which confer disease immunity. For example, a study done at Stanford showed that first shot of the Pfizer vaccine did increase SARS-CoV-2-specific antibody levels, but hardly in comparison to the second shot.3 In fact, the “booster” dose increased immune response by 100-fold and appeared to stimulate groups of immune cells – such as CD14+CD16+ inflammatory monocytes – that the first dose did not. The authors thus concluded that the second dose “mount(ed) a more potent [immune] response.”

Why is this the case? It is thought that because mRNA vaccines merely contain ribonucleic acids and not more “obtrusive” foreign bodies – such as a large protein or a neutralized virus – the second dose is necessary. Therefore, the first dose primes the immune system to be able to recognize the pathogen, whereas the second dose instigates a stronger immune response to allow for widespread generation of antibodies. This may also be the reason that people generally experience more adverse symptoms to the second dose: it has much higher reactogenecity.

Despite these findings, there is much room for progress when it comes to vaccine development and our understanding of how staggered doses impact immune response. As Stanford vaccine researcher Bali Pulendran once said, the current pandemic marks “the first time RNA vaccines have ever been given to humans, and we have no clue as to how they do what they do: offer 95% protection against COVID-19.”4


1 The Advisory Committee on Immunization Practices’ Interim Recommendation for Use of Pfizer-BioNTech COVID-19 Vaccine – United States, December 2020. (2020, December 17). Retrieved from https://www.cdc.gov/mmwr/volumes/69/wr/mm6950e2.htm?s_cid=mm6950e2_w 

2 mRNA Therapeutic Areas in Infectious Diseases. (2021). Retrieved from https://www.modernatx.com/pipeline/therapeutic-areas/mrna-therapeutic-areas-infectious-diseases 

3 Arunachalam, P. S., Scott, M., et al. (2021). Systems vaccinology of the BNT162b2 mRNA vaccine in humans. Nature, 10.1038/s41586-021-03791-x. Advance online publication. https://doi.org/10.1038/s41586-021-03791-x 

4 Henderson, R. B. (2021, July 19). Study: Second dose of COVID-19 vaccine induces a powerful boost to the immune system. Retrieved from https://www.news-medical.net/news/20210719/Study-Second-dose-of-COVID-19-vaccine-induces-a-powerful-boost-to-the-immune-system.aspx