Immune responses to pathogens involve many cells and proteins of the immune system. Early during an infection, these responses are non-specific, meaning that although they are directed at the pathogen, they are not specific to it. This is called innate immunity. Within a few days, adaptive immunity takes over; this immunity is specific to the invading pathogen. Adaptive immune responses include antibodies. A major goal of antibodies is to bind to the pathogen and prevent it from infecting, or entering, a cell. Antibodies that prevent entry into cells are called neutralizing antibodies. Many vaccines work by inducing neutralizing antibodies. However, not all antibody responses are created equal. Sometimes antibodies do not prevent cell entry and, on rare occasions, they may actually increase the ability of a virus to enter cells and cause a worsening of disease through a mechanism called antibody-dependent enhancement (ADE).
What is ADE?
ADE occurs when the antibodies generated during an immune response recognize and bind to a pathogen, but they are unable to prevent infection. Instead, these antibodies act as a “Trojan horse,” allowing the pathogen to get into cells and exacerbate the immune response.
Is ADE caused by a disease?
Most diseases do not cause ADE, but one of the best studied examples of a pathogen that can cause ADE is dengue virus. Dengue virus is one of the most common infections in the world, infecting hundreds of millions and killing tens of thousands of people each year. Unlike viruses like measles or mumps that only have one type, dengue virus has four different forms, called “serotypes.” These serotypes are very similar, but slight differences among them set the stage for ADE. If a person is infected by one serotype of dengue virus, they typically have mild disease and generate a protective immune response, including neutralizing antibodies, against that serotype. But, if that person is infected with a second serotype of dengue virus, the neutralizing antibodies generated from the first infection may bind to the virus and actually increase the virus’s ability to enter cells, resulting in ADE and causing a severe form of the disease, called dengue hemorrhagic fever.
Is ADE caused by vaccines?
On a few occasions ADE has resulted from vaccination:
- Respiratory syncytial virus (RSV) — RSV is a virus that commonly causes pneumonia in children. A vaccine was made by growing RSV, purifying it, and inactivating it with the chemical formaldehyde. In clinical trials, children who were given the vaccine were more likely to develop or die from pneumonia after infection with RSV. As a result of this finding, the vaccine trials stopped, and the vaccine was never submitted for approval or released to the public.
- Measles — An early version of measles vaccine was made by inactivating measles virus using formaldehyde. Children who were vaccinated and later became infected with measles in the community developed high fevers, unusual rash, and an atypical form of pneumonia. Upon seeing these results, the vaccine was withdrawn from use, and those who received this version of the vaccine were recommended to be vaccinated again using the live, weakened measles vaccine, which does not cause ADE and is still in use today.
Both the RSV and measles vaccines that caused ADE were tested in the 1960s. Since then, other vaccines have successfully been created by purifying and chemically inactivating the virus with formaldehyde, such as hepatitis A, rabies, and inactivated polio vaccines. These more recent vaccines do not cause ADE.
A more recent example of ADE following vaccination comes from dengue virus:
- Dengue virus — In 2016, a dengue virus vaccine was designed to protect against all four serotypes of the virus. The hope was that by inducing immune responses to all four serotypes at once, the vaccine could circumvent the issues related to ADE following disease with dengue virus. The vaccine was given to 800,000 children in the Philippines. Fourteen vaccinated children died after encountering dengue virus in the community. It is hypothesized that the children developed antibody responses that were not capable of neutralizing the natural virus circulating in the community. As such, the vaccine was recommended only for children greater than 9 years of age who had already been exposed to the virus.
Other viral vaccines that target multiple types of a virus have been safely used, including vaccines against polio (3 types), rotavirus (5 types), and human papillomavirus (9 types).
Can the new COVID-19 vaccines cause ADE?
Neither COVID-19 disease nor the new COVID-19 vaccines have shown evidence of causing ADE. People infected with SARS-CoV-2, the virus that causes COVID-19, have not been likely to develop ADE upon repeat exposure. This is true of other coronaviruses as well. Likewise, studies of vaccines in the laboratory with animals or in the clinical trials in people have not found evidence of ADE.
References
SARS-CoV-2 vaccine in nonhuman primates
Corbett KS, Flynn B, Foulds KE, Francica JR, Boyoglu-Barnum S, et al. Evaluation of the mRNA-1273 vaccine against SARS-CoV-2 in nonhuman primates. N Engl J Med 2020;383(16):1544-1555.
The induction of CD4 type 2 helper T-cell (Th2) (interleukin-4, -5, or -13) responses has previously been associated with vaccine-associated enhanced respiratory disease (VAERD) in some children who were immunized with inactivated respiratory syncytial virus and measles vaccines. To determine whether mRNA-1273 (Moderna) vaccine induced Th2 responses, researchers immunized macaques with two doses of either 10 mcg or 100 mcg of mRNA vaccine at four-week intervals and challenged the animals eight weeks later with SARS-CoV-2. Vaccination with mRNA-1273 induced robust SARS-CoV-2 neutralizing activity, rapid protection in the upper and lower airways, and no pathologic changes in the lung. mRNA-1273 induced Th1 and not Th2 cell responses.
Vogel AB, Kanevsky I, Che Y, Swanson KA, Muik A, et al. A prefusion SARS-CoV-2 spike RNA vaccine is highly immunogenic and prevents lung infection in non-human primates. bioRxiv 2020; https://doi.org/10.1101/2020.09.08.280818
Researchers reported the design, preclinical development, immunogenicity and anti-viral protective effect in rhesus macaques of the SARS-CoV-2 modified mRNA vaccine candidate, BNT162b2 (Pfizer BioNTech). Animals were inoculated with two doses of 100ug of mRNA. Seven days after the second dose, a robust Th1 response was observed, but only a minute Th2 response, consistent with the unlikely occurrence of vaccine-associated enhanced respiratory disease, which is associated with Th2 responses.
Gao Q, Bao L, Mao H, Wang L, Xu K, et al. Development of an inactivated vaccine candidate for SARS-CoV-2. Science 2020;369(6499):77-81.
Researchers developed a purified inactivated SARS-CoV-2 virus vaccine candidate (PiCoVacc), which induced SARS-CoV-2 specific neutralizing antibodies in mice, rats and nonhuman primates. The vaccine candidate was inactivated using β-propiolactone and mixed with alum adjuvant. Three immunizations using two different doses provided partial or complete protection in macaques. After vaccination, macaques were challenged with SARS-CoV-2 without observable antibody-dependent enhancement of infection or immunopathological exacerbation.
Yu J, Tostanoski LH, Peter L, Mercado NB, McMahan K, et al. DNA vaccine protection against SARS-CoV-2 in rhesus macaques. Science 2020;369:806-811.
Researchers developed a series of six DNA vaccine candidates without adjuvant expressing different forms of the SARS-CoV-2 spike (S) protein and evaluated them in 35 rhesus macaques compared with placebo controls. Vaccinated animals developed humoral and cellular immune responses, including neutralizing antibody titers at levels comparable to those found in convalescent humans and macaques infected with SARS-CoV-2. The DNA vaccines induced Th1 rather than Th2 responses. After vaccination, macaques were challenged with SARS-CoV-2 without observable enhanced clinical disease even with the suboptimal vaccine constructs that failed to protect against infection.
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