by Edward Chen

The COVID-19 pandemic has catalyzed rapid technological advancements as scientists and engineers mobilize to combat its toll on human lives. Time is of the essence, and after rigorous testing for safety and effectiveness, there are now 3 vaccines with emergency approval in the United States that are all based on relatively new concepts.

Two of the vaccines are based on messenger RNA (mRNA), a molecular work horse of the cell that serves as a go-between, copying information from DNA and transmitting those instructions to make proteins. mRNA vaccines instruct cells to make viral proteins, effectively priming our immune system to recognize and attack the real virus in the event that we get infected. This strategy was first proposed in 1995 in the context of cancer and later also studied in the context of the flu, Zika, hepatitis C, HIV, and other viruses. This is the first time that an mRNA vaccine has received authorization for widespread use.

The third vaccine, from Johnson & Johnson, takes a different strategy: Using a disabled virus, the vaccine delivers DNA encoding a characteristic viral protein. To learn more about how this vaccine was developed and how it works, we spoke with Dr. Jingyou Yu, a postdoctoral researcher working on adenovirus-based vaccines in the laboratory of Dr. Dan Barouch at Beth Israel Deaconess Medical Center and Harvard Medical School. In the following three-part interview, he describes the lab’s work on the Johnson & Johnson COVID-19 vaccine, starting from the release of the SARS-CoV-2 sequence in January 2020 to animal experiments in February 2020 and the FDA’s issuance of an emergency use authorization in February 2021.

Dr. Yu uses several scientific terms, which are defined below the videos.

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ACE2: A protein present on some human cells. The SARS-CoV-2 spike protein binds to ACE2 to gain entry into our cells.

Ad26: An adenovirus subtype used in the Johnson & Johnson COVID-19 vaccine. This vaccine uses the inactivated Ad26 virus to deliver DNA into human cells that can then create the SARS-CoV-2 spike protein. The spike protein triggers an immune response without needing the actual virus.

Adenovirus: A type of virus that can cause the common cold. The Johnson & Johnson COVID-19 vaccine repurposes this type of virus to carry viral DNA to immune cells.

Animal model: An animal that can be used to replicate an aspect of biology, such as a disease or response to treatment. An animal model also allows for testing the safety and efficacy of candidate drugs and vaccines without unnecessarily harming humans.

Antibody: A protein that recognizes and binds to an antigen. When antibodies bind to the spike protein of SARS-CoV-2, the spike protein can no longer be used by the virus to enter human cells.

Antigen: Any molecule that can be recognized by the immune system.

Chimeric virus: A virus that has been modified; for example, a virus that has been modified to not cause disease and to instruct human cells to produce the SARS-CoV-2 spike protein.

Efficacy/Protective efficacy: A measure of the effectiveness of vaccines. Efficacy can be defined differently by different manufacturers. For example, it can mean a vaccine prevents all disease a week after the second dose of a vaccine (Pfizer), a vaccine prevents all disease 2 weeks after the second dose (Moderna), or a vaccine prevents moderate disease after 2 weeks and severe disease after 4 weeks (Johnson & Johnson).

Immunogenic: Describes the degree to which a vaccine can generate an immune response. Vaccines that are more immunogenic generate a stronger and longer-lasting immune response.

Nucleic acid: A class of molecules that include the molecules that make up DNA and mRNA. Cells use DNA as a template for making mRNA and, in turn, use mRNA as a template for making proteins.

Phase 1: The first phase of human clinical trials. Researchers primarily test the safety and appropriate dosage of a candidate treatment in a small group of people.

Phase 2: The next phase of clinical trials. At this stage, researchers also look at the immunogenicity and efficacy of the vaccine, in addition to continuing the monitoring of safety (though safety is the primary concern). For the Johnson & Johnson vaccine, the single-dose Phase 1/2a clinical trial collectively enrolled around 800 people.

Phase 3: The late-stage phase of clinical trials. At this point, researchers recruit a much larger group of thousands of people, also testing for the safety and efficacy of the vaccine. For the Johnson & Johnson vaccine, the single-dose Phase 3 clinical trial collectively enrolled around 45,000 people.

Replication incompetent: Describes a virus that has had certain genes removed such that it cannot replicate anymore and cannot cause disease in humans.

SARS-CoV-2: The virus that causes COVID-19.

Spike protein (also called S protein): A special protein on the surface of the SARS-CoV-2 virus that can recognize and bind to the ACE2 molecule on human cells. This binding interaction enables the virus to enter human cells and cause disease. Vaccines work, in part, by stimulating the production of antibodies that target the spike protein. Due to its resemblance with a crown, the spike protein gives the coronavirus its name.

T cell: A type of immune cell that constantly circulates in the bloodstream. Some T cells recognize viral antigens present on the surface of our cells, which triggers the T cell to kill virus-infected cells. Together with B cells, which produce antibodies, they are the primary way by which the immune system responds more quickly to future infections with the same pathogen.

Vector: The method by which a DNA vaccine, such as the Johnson & Johnson vaccine (also referred to as a viral vector vaccine), delivers DNA to human cells. An example of a vector is a virus that has been engineered to be harmless and to deliver DNA coding for the SARS-CoV-2 spike protein to human cells (see Ad26).

This interview with Jingyou Yu, a postdoctoral researcher in Dr. Dan Barouch’s laboratory at Beth Israel Deaconess Medical Center and Harvard Medical, was conducted on April 21, 2021.

Edward Chen is a first-year Immunology MMSc student at Harvard Medical School. He’d like to share that the FDA approved a new mumps vaccine in 1967, 4 years after Dr. Maurice Hilleman began its development when his daughter became ill with the mumps virus in 1963; an MMR vaccine derived from the virus strain he collected from his daughter is still in use today.

Cover Image by torstensimon from Pixabay.

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2 thoughts on “How do COVID-19 vaccines work? Hear from a researcher who helped develop the Johnson & Johnson vaccine.

  1. Blah blah blah, 1st.. if the mRNA produce the protien, and now we KNOW those protiens are attaching to cells in our body (as the spike protien naturally does) what mechanism is their to prevent an immune system from attaching cells that have that protien now attached??? I haven’t heard anything about this except people claim the protiens stay localised.. but we know they don’t all stay localized. People monitoring platelet counts are seeing regression in count due to these mechanisms. This meand for many the adverse reactions are going to take time, possibly even years, to show.

  2. Very well said! Just wanted to let you know that your article has made my day. Because I was looking for these solutions for the past many days. I’ve been working in a medical billing company for over a decade now. I was really looking for such valuable insights regarding COVID vaccine billing. I would encourage you to produce such content in future as well because the healthcare industry is witnessing constant changes in terms of the latest billing and overall guidelines regarding different COVID Vaccines. So, in this fast-paced era, making efforts to keep your readers at the top of changes is truly a great contribution.

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