Haste plus speed: the need to ensure COVID-19 vaccines don’t make infections worse

How COVID-19 vaccine developers can lower the risk of being derailed by antibody-dependent enhancement

The rush to make a vaccine for COVID-19 has raised concern that some candidate treatments could make infections worse. The main risk is the chance of inducing antibody-dependent enhancement, a process known to complicate vaccine development in Dengue and several other diseases.

The topic drew attention at a global online forum sponsored last month by WuXi Apptec Co. Ltd. (Shanghai:603259; HKEX:2359) (see "Plotting a Scientific Path to Counter COVID-19").

ADE is usually triggered by non-neutralizing antibodies or sub-neutralizing levels of antibodies.

Two papers published in Cell and the Journal of Virology in February showed it can happen with neutralizing antibodies as well.

While it’s too early to know if COVID-19 carries a risk of ADE, other coronaviruses, including SARS-CoV and MERS-CoV, have been associated with the phenomenon, Scott Halstead, who introduced the ADE concept 40 years ago, told BioCentury.

This does not make ADE a foregone conclusion with COVID-19, Halstead noted. “There is a huge difference between the possibility that a vaccine will sensitize a susceptible (seronegative) recipient to an antibody-enhanced disease and the reality that it actually does.” Halstead is an adjunct professor at the Uniformed Services University of the Health Sciences.

“There is a huge difference between the possibility that a vaccine will sensitize a susceptible, seronegative recipient to an antibody-enhanced disease and the reality that it actually does.”

Scott Halstead, USUHS

For SARS and MERS, antibodies against the viruses -- elicited either by infection or vaccination -- have been shown to cause ADE in animal models, including non-human primates. In cell cultures, they have been shown to potentiate infection of primary human macrophages.

There’s also evidence that feline infectious peritonitis virus, a coronavirus that infects domestic cats, is enhanced both by maternal antibodies transferred to kittens and by vaccination, resulting in severe and fatal feline disease.

Halstead is unaware of any “evidence that severe or fatal SARS or MERS result from antibody-mediated infections.”

Vaccine developers "must be aware of and look for" the possibility of ADE caused by COVID-19 vaccines, he cautioned.

In Dengue, the phenomenon has held up vaccine development for several drug developers (see “Dengvaxia’s Warning”).

Johan Van Hoof, global therapeutic area head for infectious diseases and vaccines at Janssen unit of Johnson & Johnson (NYSE:JNJ), told BioCentury that ADE is linked to an imbalance of responses of two types of T cell, Th2 vs Th1, favoring the former.

Van Hoof thinks companies could use this fact during Phase I testing to demonstrate a low risk of ADE by showing their candidate induces a Th1-driven immune profile. Showing a vaccine candidate elicits neutralizing antibodies will also be important, he said.

Figure: Antibody-dependent enhancement and strategies to avoid it

Preclinical studies in MERS-CoV and SARS-CoV, as well as research on cat coronaviruses, have raised the possibility that COVID-19 vaccines might cause antibody-dependent enhancement (ADE) of subsequent infection, making the disease more instead of less severe.

The majority of COVID-19 vaccines in development aim to elicit neutralizing antibodies against the spike protein that prevent the virus from binding ACE2 on lung cells and entering via endocytosis.

However, some antibodies, especially non-neutralizing antibodies, can enhance disease by binding to the virus and Fc receptors on monocytes, macrophages and other immune cells, enabling viral uptake by cells that don't express ACE2. The result is additional viral replication, and a skew toward Th2 rather than Th1 immune responses.

Antibodies against another coronavirus, Middle East respiratory syndrome coronavirus (MERS-CoV), have been shown to cause ADE in animals by an additional mechanism: complement activation, which further increases pulmonary inflammation and immune cell recruitment.

At least four vaccine design approaches that could avoid ADE have been proposed in the literature (bottom).

A Journal of Virology study in February noted that some anti-spike neutralizing mAbs bind epitopes outside the protein's receptor-binding domain (RBD), and suggested designing subunit vaccines without the domain as a way to focus the immune response on other neutralization epitopes.

Immunofocusing constitutes one of the main methods proposed to prevent ADE and skew adaptive immunity toward protective responses. Other immunofocusing strategies include masking undesired antibody epitopes with glycosyl groups; truncating the spike protein; and locking the antigen into conformations that display epitopes for neutralizing antibodies.

Source: Scientific literature

Designing out ADE

A variety of vaccine design approaches have been proposed to help lower risk for ADE.

Most companies developing COVID-19 vaccines have not said whether they are using these or other approaches.

Kizzmekia Corbett, scientific lead of the coronavirus team at NIH’s vaccine research center, previously told BioCentury that the candidate from Moderna Inc. (NASDAQ:MRNA), mRNA-1273, which encodes the virus’ spike protein, incorporates mutations that stabilize the spike in a prefusion conformation to ensure it induces the right kind of antibodies to confer protection.

Peter Hotez, co-director of Texas Children’s Hospital Center for Vaccine Development at Baylor College of Medicine, told BioCentury his team’s strategy involves “reducing the size of the subunit vaccine” to focus the immune response on the receptor-binding domain of the spike protein.

CureVac AG spokesperson Thorsten Schüller told BioCentury the company took into account preclinical and animal data regarding coronavirus-associated ADE “for the design of our vaccine candidates for SARS-CoV-2 by carefully selecting the target protein.” He declined to disclose the details.

Janssen spokesperson Paul Graves told BioCentury the company is exploring approaches that "target all or some parts of the protein" for its vaccine and "will select which targets to pursue based on the results of our early research."

Moderna’s mRNA-1273, partnered with NIH, will be among the first preventative vaccines to enter the clinic; it is scheduled to start Phase I testing Friday. The first clinical batch of mRNA-1273 was delivered 42 days after the genome of the virus that causes COVID-19 was released; design and manufacturing took 25 days.

CureVac hopes to have an mRNA vaccine in the clinic by June or July, and Janssen plans to take a candidate from its recombinant adenovirus (rAdV) vector platform into the clinic within a year.

More than three dozen companies and academic groups have announced COVID-19 vaccine programs (see “A Growing List of Vaccines” and “U.S. Testing of Coronavirus Vaccine, Therapeutic Begin”).

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