Immune Response From mRNA COVID-19 Vaccines Is More Robust Than Natural Infection


Antibody levels induced by mRNA COVID-19 vaccines are much higher than those induced by natural infection and confer cross-reactivity that could be effective against new variants, a new study from the University of California, Irvine, found.


The antibody response induced by mRNA vaccination against coronavirus disease 2019 (COVID-19) is stronger and more variable than that of natural infection, a new study found.

The study, published on the bioRxiv preprint server, used data from ongoing seroprevalence studies in Orange County, Calif., before and after a campaign to administer mRNA vaccines.

“MRNA vaccine induced antibody levels are spectacular and appear rapidly within a few days after vaccination,” corresponding author Philip Felgner, PhD, professor in residence and director of the Vaccine R&D Center at the University of California, Irvine told Contagion. “Only in our dreams we could have imagined a vaccine that that could be developed so quickly, works so well, can be manufactured at scale, distributed and administered to billions of people worldwide within months.”

The study included a cohort of 6724 health care workers from the University of California Irvine Medical Center, who were vaccinated within 3 weeks as part of an intensive vaccination campaign that began Dec. 16. It also included participants in a countywide study in Orange County and a focused community study in Santa Ana.

Before the vaccination campaign, seropositivity among health care workers increased from 4.5% in May to 13% in December. After vaccination, seropositivity rose to 78% by the last week of January, 93% by the last week of February and 98.7% by the last week of March.

“Ab levels induced by the vaccine are much higher than levels induced by natural exposure and infection,” Felgner said. “The vaccine also induces cross reactive Abs against other novel CoV strains that are not induced by natural exposure and infection. This offers hope that the vaccine will be effective against emerging virus variants that are circulating around the world.”

The vaccines induced robust reactivity levels, including antibodies against the full-length spike protein, S1 and S2 subunits, and the receptor binding domain (RBD) of the SARS-CoV-2 spike protein, which binds to the angiotensin-converting enzyme 2 (ACE2) receptor on host cells. Cross-reactive antibodies between the spike protein and RBD induced by the vaccine could possibly provide protection against emerging variants.

This differs from the response from natural infection, which had weak antibody levels against RBD but produced the highest levels of antibodies against nucleocapsid protein (NP) antigens. Anti-nucleocapsid antibodies weren’t affected by the vaccines and could indicate prior natural exposure.

After the second dose of the vaccine, antibody titers were up to 10 times higher than those of patients who had recovered from natural COVID-19 infection, suggesting that even those with prior exposure could benefit from vaccination.

The study also found that people who have had prior exposure to SARS-CoV-2 had a stronger immune response to the vaccine, developing antibody levels faster than those who hadn’t been exposed to the virus.

Weekly monitoring of 9 individuals before and after vaccination showed differences in responses to first and second doses of the vaccine and suggested that for many individuals a more robust response only occurred after the second shot.

Felgner said further research is needed to discover ways to boost immunity in immune compromised individuals, who do not develop high antibody levels after vaccination. Further research also is needed to measure the duration of immunity and to compare immune responses of different vaccines.

“Nucleic acid vaccination was discovered 30 years ago,” Felgner said. “Thirty years of scientific discovery by hundreds of scientists, clinical development and manufacturing supported with billions of dollars from the NIH and several companies led to the outcome we’re experiencing today, and saving the world.”

Pfizer announced recently that individuals who received the BNT162b2 COVID-19 vaccine will most likely need a third dose within 12 months of being fully vaccinated, and annual vaccinations may be necessary.

After the success of its COVID-19 vaccine, Moderna announced that it has 14 different mRNA vaccines in clinical trials for viruses including respiratory syncytial virus (RSV), cytomegalovirus (CMV) and human immunodeficiency virus (HIV).

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