In an amazing feat of human ingenuity and teamwork, the first COVID-19 vaccine was designed, developed, tested, and authorized for emergency use in December 2020. Not only was this normally lengthy process completed in less than a year, it also introduced the novel use of modified mRNA to induce an immune response against an infection. These mRNA vaccines effectively generate antibodies and prevent infection and hospitalization. However, scientists did not know how mRNA vaccines compared to more common vaccine methods nor the mechanism by which COVID-19 vaccines induced long-term immunity.

COVID-19 vaccine vials
Researchers compared multiple COVID-19 vaccines to compare efficacy and long-term immunity.

To answer these questions, Shane Crotty and his group at the La Jolla Institute for Immunology performed a head-to-head comparison of four currently used COVID-19 vaccines that target the SARS-CoV-2 spike protein: Pfizer/BioNtech (mRNA), Moderna (mRNA), Janssen/J&J (adenovirus), and Novavax (recombinant protein). In a six-month longitudinal study published in Cell, the researchers examined blood samples from vaccinated and recently infected people for SARS-CoV-2 spike-specific immune responses.

In this study, Crotty sought to standardize the methods by which scientists compared these different vaccines. While it’s clear that mRNA vaccines are successful, comparing vaccines in different scientific studies using multiple types of assays remained a challenge. “We spent 15 months recruiting people and collecting samples so that we could actually run everything in the same labs, on the same machines with controls, so we could really do the head-to-head, high-quality comparison across four different vaccines, which was a big deal, but also against three different kinds of vaccines, which was an even bigger deal,” said Crotty. 

Crotty’s experiments revealed some striking results. When compared to samples from primary infections, all vaccines were just as, if not more, effective in inducing a SARS-CoV-2-specific long-term immune response that lasted up to six months. By analyzing the presence of memory B and T cells and measuring their response to in vitro SARS-CoV-2 infection, the researchers found that mRNA vaccines are just as effective as the traditional protein-based vaccination methods. They also found some notable differences between the vaccine types. “The most exciting data was to see that in the B cell side of the story, we saw that a g-coupled chemokine receptor called CXCR3 was increased in memory B cells in response to the adenovirus-based vaccine,” said Camila Coelho, a researcher in the Crotty lab and an author of the study. The researchers did not see this phenomenon in the mRNA vaccinated patients. According to Crotty, the consequences of this are still unknown, but these similarities and differences highlight the fact that there is still much to learn about the immune system and vaccine efficacy.

We can go forward with this as a common way of making vaccines against new systemic infections.
- Suresh Marulasiddappa, University of Wisconsin-Madison

“I think this has confirmed that the mRNA vaccines are actually a pretty good deal,” said Suresh Marulasiddappa, a professor of immunology at the University of Wisconsin-Madison, who was not involved in the study. “We can go forward with this as a common way of making vaccines against new systemic infections.”

The Crotty lab has big plans for the future. “We are interested in the durability of immunity in people who received the booster and also who get breakthrough infections,” said Zeli Zhang, a postdoctoral fellow working with Crotty and the first author of the study. “We would like to see what the immunity in these people looks like after six months…or even one year.”


  1. Z. Zhang et al., “Humoral and cellular immune memory to four COVID-19 vaccines,” Cell, 185(14):2434-51, 2022.
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