How do the various COVID-19 vaccines work, and when should patients be vaccinated? We tackle these topics and more in this episode.

Our host David H. Henry, MD, is joined by Drew Weissman, MD, PhD, a professor at the University of Pennsylvania, Philadelphia. Dr. Weissman codeveloped the messenger RNA (mRNA) technology being used in the COVID-19 vaccines produced by Pfizer/BioNTech and Moderna.

History of mRNA vaccines

• Testing of mRNA vaccines began in the 1990s.
• An initial problem with these vaccines was that the RNA was highly inflammatory.
• Dr. Weissman and his colleague, Katalin Karikó, PhD, discovered how to fix that problem in 2005.
• The pair found that placing modified nucleosides into mRNA made it noninflammatory and allowed for increased production of protein from the RNA – up to a 1,000-fold increase in mice.
• This technology is the basis of the Moderna and Pfizer/BioNTech COVID-19 vaccines.

Immunology and vaccines

• To produce a good immune response, antigen must be present for a long time, though the optimal amount of time is unknown, Dr. Weissman said.
• The mRNA lipid nanoparticles (LNPs) used in the COVID-19 vaccines make protein for 10-14 days, resulting in a “great” immune response, according to Dr. Weissman.
• Most vaccines have an adjuvant, or something that stimulates the immune response by inducing TH1 or TH2 responses.
• The LNP used in the COVID-19 vaccines is an adjuvant that makes a specialized CD4 helper cell that drives antibody production, increases antibody affinity, and matures antibodies to make long-lived plasma cells to allow for long-lived antibody responses.
• This is the only adjuvant known that induces these type of helper T cells.

COVID-19 vaccine reactions

• Adverse reactions to COVID-19 vaccination – flu-like symptoms, arm pain, etc. – are caused by the LNP, not the spike protein.
• Once the LNP is gone, usually within the first 24 hours, symptoms dissipate.
• The amount of spike protein produced decreases over 14 days.
• It’s unclear if patients should take NSAIDs to manage symptoms after COVID-19 vaccination, as this hasn’t been tested.
• However, with influenza vaccination, taking an NSAID will decrease the immune response.

Variants and their impact on vaccination

• SARS-CoV-2 variants have been reported in Brazil, South Africa, California, and the United Kingdom.
• Dr. Weissman explained that there are two kinds of variation: when a virus learns how to better infect people and when the virus learns to avoid immune responses.
• Most SARS-CoV-2 variants are equally addressed by the vaccines, though we know vaccines have reduced efficacy against the South African variant, Dr. Weissman said.
• The good news is that coronavirus mutates very slowly, and it’s easy with mRNA vaccines to “plug in” a mutant and make a more effective vaccine, Dr. Weissman said.

Vaccinating cancer patients: Treatment considerations

For patients receiving chemotherapy:

• We don’t know the best time to administer COVID-19 vaccines to patients on chemotherapy, as this hasn’t been studied, Dr. Weissman said.
• When other vaccines were given to subjects receiving chemotherapy, those vaccines did not work as well.
• Chemotherapy knocks down myeloid cells around day 7, with recovery typically around day 28.
• Dr. Weissman said he would probably vaccinate at day 14 in the chemotherapy cycle, as the germinal centers where B cells are produced form about 2-7 days after receipt of the vaccine.

For patients receiving checkpoint inhibitors:

• The optimal time for vaccination in patients receiving checkpoint inhibitors is unknown.
• However, the immune response to vaccination in patients on checkpoint inhibitors is expected to be similar to the general population or slightly enhanced.

For patients receiving anti-CD20 antibodies:

• Anti-CD20 antibodies might blunt the B-cell response to vaccination.
• Rituximab, for example, depletes B cells in the circulation for months.
• In the absence of B cells, there won’t be a good antibody response.
• T-cell response is also stimulated by COVID-19 vaccines, but we don’t know how effective that response will be in protecting against infection, Dr. Weissman said.

Vaccinating HIV patients

• Patients with well-controlled HIV (i.e., low viral load and CD4 counts >200) should generate a good immune response, Dr. Weissman said.
• Patients with poorly controlled HIV (i.e., high viral loads and low CD4 counts) are likely to have a poor immune response to vaccination, though it isn’t clear how poor the response will be.

Should patients who recently had COVID-19 get vaccinated?

• Clinicians are waiting 90 days to vaccinate patients who have a positive COVID-19 test, Dr. Weissman said.
• In 95% of cases, SARS-CoV-2 infection conveys protective antibodies for at least 3 months.
• Patients with recent SARS-CoV-2 infection have more severe adverse reactions to vaccination (e.g., fever, arm pain, flu-like symptoms).
• It’s safe to wait until 2 weeks after recovery from infection before receiving the vaccine, and vaccination is expected to work well with a boosted immune response, Dr. Weissman said.

Is there any role for checking antibody status after vaccination?

• Phase 3 trials of the Pfizer/BioNTech and Moderna vaccines showed that levels of neutralizing antibodies were higher in vaccinated patients than in those who had recently been infected; i.e., vaccines give a better immune response than infection.
• The durability of response to the vaccines is unknown, but studies are underway.
• The challenge for clinicians is that the antibody assays available are not directed at the spike protein, and they are not quantitative.

Vaccine on the horizon

• The COVID-19 vaccine under development by Johnson & Johnson uses adenovirus.
• The spike protein is inserted into the genome of the adenovirus, and the virus is altered so it cannot replicate, thus preventing its spread.
• The live virus stimulates the cells to make a better immune response.
• This type of vaccine is potent and produces lower antigen levels than mRNA vaccines but with better T-cell responses, Dr. Weissman said.
• On Jan. 29, Johnson & Johnson released phase 3 data for this vaccine (https://bit.ly/3oNXX1k).
• The vaccine was reported to be 85% effective overall in preventing severe COVID-19.

Show notes written by Sheila DeYoung, DO, a resident at Pennsylvania Hospital, Philadelphia.

Disclosures

Dr. Weissman disclosed royalties from Moderna and Pfizer/BioNTech. Dr. Henry has no disclosures.

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