COVID-19 vaccine 101: Dr. Drew Weissman discusses mechanisms, efficacy, and vaccinating patients with cancer or HIV

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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