The first wave of COVID-19 vaccines was tested in record time — a Herculean effort supported by over $2 billion in the United States alone, and tens of thousands of trial volunteers worldwide. Now, scientists and government bodies are exploring strategies to make it faster and cheaper to test future vaccines in a wider range of participants.

Project NextGen, a collaboration between the Center for Biomedical Advanced Research and Development Authority (BARDA) and the National Institute of Allergy and Infectious Diseases, will leverage public-private partnerships to develop new vaccines and therapeutics to better protect against current and future SARS-CoV-2 variants.

Recently, a team of biostatisticians led by Fred Hutch Cancer Center’s Peter Gilbert, PhD, to identify correlates of protection (molecular shorthands that stand in for vaccine efficacy) for COVID-19 vaccines being tested through Project NextGen.

The Fred Hutch team will outline these immune signatures for several new types of COVID-19 vaccines as well as assess decentralised vaccine trial designs that could expand vaccine trial access while lowering costs.

“Our previous studies to evaluate immune correlates were done for injected vaccines, so the NextGen studies will teach us whether the immune correlates need to be updated for the new types of vaccines,” said Gilbert, who has dedicated his career to developing and implementing the statistical methods that reveal important immunological signatures in blood samples of vaccine trial participants.

Supported by the Rapid Response Partnership Vehicle (RRPV) Consortium, Gilbert’s team will assess data from Phase 2b trials of new COVID-19 vaccine modalities, including an oral pill and a nasal spray. The assessments of the decentralised trials will help determine whether at-home blood collection provides the information needed to confidently assess vaccine efficacy, as well as whether at-home or at-pharmacy collection strategies help reduce barriers to vaccine trial participation.

BARDA, a program of the Administration for Strategic Preparedness & Response (ASPR) within the Department of Health and Human Services, is tasked with developing the tools and drugs the country needs to respond to public health emergencies, including future pandemics. Project NextGen, an outgrowth of Operation Warp Speed, facilitates the development of medical countermeasures against current and future public health security threats like coronaviruses.

Large, randomised trials that compare the rate of infectious disease between randomised groups still stand as the gold standard approach to learning whether new vaccines work, Gilbert said.

But these are expensive trials that require many thousands of participants and take months to return results. To accelerate the testing of new vaccines, scientists use immunological signatures that stand in for gold-standard efficacy endpoints.

“Immune correlates are immunological biomarkers measured from blood samples that can be used to reliably predict how well vaccines work,” Gilbert said.

The presence of a protective biomarker predicts whether a participant will have a good and protective response to the vaccine, noted Fred Hutch Senior Staff Scientist Jessica Andriesen, PhD. Conversely, she said, a vaccine that fails to promote the key biomarker is unlikely to protect well. (And some biomarkers, called correlates of risk, predict a higher likelihood of disease, Andriesen noted.)

Immunological signatures such as the patterns of antibody responses, arise in the blood within weeks of vaccination. Once scientists outline a vaccine’s immune correlate or key antibody pattern, they can use that signature to determine whether a vaccine will be protective in a much shorter time frame, Andriesen said.

“So the trial is smaller and shorter, it’s cheaper and faster, and we get more public health information and science,” she said.

Assessing whether antibody biomarkers perform well as correlates of protection is the Fred Hutch team’s speciality. If the biostatisticians validate the biomarkers as correlates of protection in the latest suite of trials, it means the biomarkers are strong and can underpin public health decision-making (such as regulatory approval), Gilbert said.

The Fred Hutch group will address whether the new oral and nasal versions of COVID-19 vaccines elicit the same protection-correlating immune signatures as previous COVID-19 vaccines, or whether they prompt different signatures that need to be defined.

To ensure that vaccines work, they need to be tested in as wide an array of people as possible. In most vaccine trials, volunteers have their blood drawn in a clinical setting, but constraints in scheduling and commuting can make it difficult for many people to participate in these trials. To get more people involved, scientists are testing strategies that require less effort, less blood and — hopefully — fewer phlebotomy needles.  

To make it easier for more people to participate in vaccine trials, BARDA is testing out a decentralised approach: the REMOTE (REimagining Measurements and Operations of Translational Endpoints) trial. The immune correlate here is already defined (trial volunteers will receive a U.S. Food and Drug Administration-licensed COVID-19 vaccine). Instead, it’s the collection approach that is being assessed.

“The decentralised NextGen trials assess proof-of-concept of whether an immune correlate can be successfully characterised based on a decentralised design,” Gilbert said.

Participants will donate blood either in a clinical setting or through a device that can take a tiny blood sample at home. Previous immune correlates were defined using generous blood samples: in clinical settings, volunteers generally donate about 10 millilitres (about two teaspoons) of blood. This nets researchers about one teaspoon of serum, the clear fluid that contains antibodies. At-home collection devices scale this down dramatically, drawing less than 0.4 millilitres of blood, a volume that’s about 25 times smaller.

Serum-wise, “this is like a teaspoon versus a raindrop,” Andriesen said.

That’s great news for people who dislike needles, but whether that minuscule amount of serum contains enough antibody information to define correlates of protection remains to be seen.

If successful, the REMOTE trial will validate the idea that blood samples in vaccine trials can be collected at home. To facilitate this, the Fred Hutch team will develop new statistical methods to analyse the antibody information extracted from smaller serum samples, Andriesen said.

The team will also analyse data from a pharmacy-based decentralised trial. This trial aims to meet people in their own neighbourhoods (or local Walgreens).

“You’re not reaching out to people, you’re meeting them when they come in [to the pharmacy],” Andriesen said.

In this case, the trials aren’t testing different ways to collect blood samples, but whether more people will participate in a clinical trial if they can bundle steps like vaccination and blood donation with a trip they’re already making to the drugstore.

“Decentralised trials are promising for increasing the pace of enrollment and also the breadth of representation of diverse populations,” Gilbert said.