Immunogenicity studies for the coronavirus vaccines: How to stay on track and build testing capacity even during COVID-19

As the world waits for a vaccine to protect against COVID-19, the disease caused by the novel coronavirus, it will need not only scientific excellence but also business continuity excellence to keep vital research and immunogenicity studies running.

Vaccine development relies on many early, nonclinical studies; some of the earliest of which are immunogenicity studies. These studies investigate the immune response to the therapeutic protein in a potential vaccine and examine its clinical impact.

But how can we keep these studies on track when social distancing is required and test systems may be limited? Learn how to execute existing immunogenicity studies and expand study capacity for potential COVID-19 vaccines even during a crisis.

Supporting COVID-19 vaccine development with immunogenicity studies

Immunogenicity is defined as the ability or the extent to which a substance stimulates an immune response. As part of the preclinical testing program, immunogenicity studies consider the pathogen’s lifecycle and immunology.[1]

In the case of COVID-19, the infectious agent is SARS-CoV-2, a novel member of the coronavirus family. The genome of SARS-CoV-2 is 96% identical to a coronavirus found in bats, and 79.6% identical in sequence to SARS-CoV, the pathogen that causes Severe Acute Respiratory Syndrome.[2] SARS-CoV-2 cycles between humans and animal hosts, including bats and possibly pangolins (a scaly anteater found in Asia and Africa). While the infection in humans mostly causes mild symptoms, some people may develop more severe symptoms, including trouble breathing, or pneumonia, which may be fatal, so the need for a vaccine is crucial.

Stimulating an immune response

SARS-CoV-2 interacts with its human host by binding to ACE2 receptors in lung epithelial (and other) cells. The virus enters the host cell and viral RNA is translated into proteins. New viruses are formed, which leave the cell, and carry on the cycle of infection.

The immune response kicks in after recognition of the virus by antigen-presenting cells (APCs) and the recruitment of T-helper cells, which call on the actions of B cells and killer T cells. B cells produce neutralizing antibodies of the IgG and IgA class, so that the virus can no longer enter and infect cells. Cells that are infected are killed by cytotoxic T cells.

Circulating B cells and T cells with memory of the virus are expected to give immunity, but for how long, and whether re-infection is possible, is unknown at this time. Immunogenicity studies assess these responses in order to provide potential answers to these questions.

Vaccine production involves choices about which antigen(s) to select as the immunogenic stimulus. SARS-CoV-2 is an encapsulated RNA virus with a distinctive crown (corona) of spike (S) proteins as well as M (membrane) and other proteins. The whole virus, inactivated or weakened, may be used. Alternatively, the constituent proteins or nucleic acids may serve as the antigens. 

Refining the dosage and pursuing efficacy

Each type of vaccine has its advantages and disadvantages. For example, some subunit vaccines may be only weakly immunogenic and require repeated doses, while repeated doses of DNA vaccines may cause toxicity.[3]

In one successful example of a preclinical subunit vaccine being developed against COVID-19, microneedles loaded with the S1 spike protein of the SARS-Cov-2 virus stimulated an IgG response in mice two weeks after subcutaneous inoculation.[4]

Just getting an initial IgG response isn’t enough though. After inoculation with test vaccines, sample analysis is required to assess for either, or both, T- and B-cell responses. Common platforms, such as ELISA, ELISpot and others allow researchers to make decisions on which candidate, dose, adjuvant, etc to move forward into further stages of development. 

Stimulation of an antibody response in animals is technically a sign of immunogenicity, but not a guarantee of efficacy. However the antibody response and clinical effect is generally well-correlated and therefore, a robust and well-conducted preclinical testing phase, where immunogenicity is tested and explored, is crucial for clinical vaccine testing.

Both immunogenicity and efficacy testing can be conducted in the preclinical phase with a variety of animal models and species. Rodent, rabbits and NHPs are often the most suitable species for immunogenicity studies; while ferret, cotton rat, NHP and a variety of others are used in testing efficacy.

Keeping immunogenicity studies on track during a crisis

With over 10 million confirmed cases globally and more than 500,000 confirmed deaths at the time of publication (see John Hopkins map for current statistics), the vast majority of vaccine research at the moment is dominated by COVID-19 with more than ninety vaccines in development across the world.

Most of this research is being funded by private or industrial firms. One source indicates that thirty pharmaceutical companies are working on coronavirus treatment therapies with nine clinical trials underway. In the US, there are partnerships funded by the Biomedical Advanced Research and Development Authority (BARDA). In the UK, Oxford University has teamed up with Astra Zeneca. The Coalition for Epidemic Preparedness Innovations (CEPI) has multiple active global partnerships focused on COVID-19 vaccine development and production.

Ironically, the search for a coronavirus vaccine could be delayed by the very processes in place to stop its spread. Social distancing is reducing the ability of some companies to conduct immunogenicity studies efficiently.

In addition, the focus on vaccines to SARS-Cov-2, has led to existing studies for vaccines to other diseases being put on hold or cancelled. Even in the midst of COVID-19, there is still a need for effective vaccines to be developed against longstanding diseases such as malaria and cholera or lesser known threats such as Lassa, Nipah, Disease X, Rift Valley Fever and Chikungunya disease, highlighted by CEPI and the WHO.    

Only companies with well-established business continuity plans and systems can overcome these vaccine development challenges, ensuring continued operational effectiveness and even expanded capacity.

Choosing a drug development partner with a strong business continuity plan for your immunogenicity studies

Contract research organization and other drug development companies who wish to continue advancing COVID-19 research need to embrace and adopt a business continuity plan (BCP) in order to maintain immunogenicity testing services and support research and treatment development for the coronavirus.

Agile vaccine development and research organizations will have

• Analyzed the impact of any disruption to key services.
• Considered the response to the expected incident(s) considering
  • What would it take to control and contain the situation.
  • What the expected resource cost and time frame might be.
  • What recovery might look like, in terms of the new incident-proof service provided.
• Assessed the likely and plausible risks and model threats and outcomes.
• Ensured these plans are accepted and understood across the company, so they can be actioned effectively at short notice.

We are ready now to partner with you on current and future development challenges

In times of crisis, the bridge between preclinical and clinical testing of medicines must be maintained. There needs, however, to be more than excellence in science, as smaller companies and providers have found in trying to pursue their vaccine development programs.

Over the last several months, we have implemented significant business continuity responses to maintain and be able to continue expanding our preclinical immunogenicity testing services. Below is a quick highlight of some of the changes we’ve already made.

Examples of the BCP incident-response enabling maintenance of immunogenicity testing during lockdown

• Three-shift operation that allows physical distancing while maintaining operations.
• Built in redundancy at every level, including
  • Multiple vivariums on site
  • Backup vivarium room washers
  • Additional research model vendors
  • Possibility to leverage colleagues globally should additional trained and qualified staff be needed.
• Maintained focus on animal care which is paramount to our operations; we are accredited by the Association for Assessment and Accreditation of Laboratory Animal Care International (AAALAC International).

Partnership with an established CRO with a solid business continuity plan is essential in carrying on operations.

While we all wish that COVID-19 will be contained and never returns, there is the possibility that future waves of SARS-Cov-2 will come. Scientific research must continue, and we are ready to deliver.