Scientists are inching closer to understanding how antibodies and immune cells are unleashed by the body in response to the novel coronavirus.

Why it matters: Natural immunity differs from that afforded by vaccination but it offers clues for the design of effective vaccines and therapies.

Driving the news: The FDA earlier this week issued guidance on evaluating COVID-19 vaccines, placing an emphasis on assessing safety and efficacy through clinical trials.

• That is standard procedurein the development of a vaccine, but the agency doubled down on its message in a climate of compressed timelines and as misinformation and skepticism of vaccines spread.
• The FDA established a benchmark that a COVID-19 vaccine "would prevent disease or decrease its severity in at least 50% of people who are vaccinated."

Where it stands: Vaccine development typically centers on creating an antibody response to prevent infection from a virus. Here's the latest on the antibody response to SARS-CoV-2, the virus that causes COVID-19:

• Most people who recoverproduce some antibodies to the virus, some of which are neutralizing antibodies that block the virus from entering cells.
• The amount and type of antibodiesappear to varyby person. In one pre-print study, not yet peer-reviewed, researchers looked at convalescent plasma and found a wide range. Most had only a modest level of antibodies, and roughly 16% didn't have neutralizing antibodies, but 10% had very strong neutralizing activity, says Larry Luchsinger of the New York Blood Center and an author of the study. They found the differences couldn't be chalked up to age, blood type or ethnicity — but men had twice as much antiviral activity.
• In another recent peer-reviewed study, the amount of neutralizing antibodies was low in more than 99% of the participants but small amounts of antibodies that bind the virus' receptor binding domain were found in all the participants, suggesting humans are "intrinsically capable" of generating antibodies that neutralize SARS-CoV-2, the authors wrote in Nature.
• People with severe infectionsappear more likely to develop antibodies. "If you have evidence of more inflammation ...then your antibody levels tend to be higher," says Sanjeev Krishna, of St. George’s, University of London, who is a co-author of a different pre-print study that looked at the levels of a different antibody (IgG) to the virus in 177 people over time.
• But not everyone produces antibodies, according toseveral recent studies. Krishna said they found 2%–8% of people infected with the virus didn't test positive for IgG antibodies.

Between the lines: For those who do develop antibodies, it's too early to sayhow long the antibodies will last and whether they will confer protection, Daniel Lingwood of Harvard Medical School tells Axios.

• Krishna's study showed no decline after almost two months.
• But a recent study published in Nature Medicine looking at 37 asymptomatic people and 37 symptomatic people found a decline in levels of both IgG and neutralizing antibodies after two or three months. (The amount was more reduced in people without symptoms.)

Meanwhile, the body's other immune actors for fending off viruses are increasingly receiving attention.

• Helper T cells assist the body in remembering the targets for antibodies they deploy. Researchers are finding many people who recover from COVID-19 have helper T cells that target specific proteins on SARS-CoV-2.

Another type of T cell — killer T cells — is at the heart of the separate cellular immune response. These longer-term immune actors arrive a bit later in the process and help tamp down an infection and its severity by killing infected cells rather than protecting against infection.

• A small study of patients admitted to the ICU for COVID-19 complications found the majority had SARS-CoV-2-specific killer T-cells.
• Two of the healthy control subjects who were not exposed to the virus also had low levels of T cells that react to SARS-CoV-2, "indicative of cross-reactivity due to past infection with ‘common cold’ coronaviruses," the authors write.

It's no surprise that T cells are important, as they're known to help combat a host of different viral infections, says Mark Poznansky, director of the Vaccine & Immunotherapy Center at Massachusetts General Hospital.

• Yes, but: It's still unknown how long the T cell responses last, whether they prevent infection with SARS-CoV-2, and if the virus can evade them (and antibodies).

What to watch: "We don't know what protective immunity is, and therefore we don't know exactly what needs to be re-created to protect you," Poznansky says.

• T cells and the proteins they target on viruses should be considered as well as antibodies in vaccine design, he and other researchers urge.
• A successful vaccine will depend on it working in a clinical study, not necessarily on the level of antibody response.
• "The unknowns of immunity are overridden by whether it’s actually clinically working,” Poznansky adds.

The bottom line: Antibodies aren't the be-all and end-all for the immune system — and they aren't likely to be for COVID-19 vaccines.

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