Question: Can previous Dengue Infection make you more susceptible to Dengue or does it make you develop an immunity to dengue?
One of the common questions on dengue infections and may have been the root of the Dengvaxia controversy in the Philippines was the threat of previous patients cured of dengue to be more prone to another dengue infection. To analyze this, we have to take a look at the virology of the dengue virus.
It is not entirely clear why secondary infection with a different strain of dengue virus places people at risk of dengue hemorrhagic fever and dengue shock syndrome. The most widely accepted hypothesis is that of antibody-dependent enhancement (ADE)
What is Antibody-dependent Enhancement?
A 2003 study by Tirado, S. and co authors on Viral Immunology states that Antibody-dependent Enhancement (ADE) is a phenomenon in which binding of a virus to non-neutralizing antibodies enhances its entry into host cells and sometimes also its replication.
We review some basic immunology first to explain its mechanisms.
The Principles of Virology book published in 2015 explained that in order to enter cells, virus particles and intracellular bacteria use molecules on their surfaces to interact with the receptors on the surface of their targets which allows them to enter these cells and start their replication cycle.
Neutralizing antibodies can inhibit the infectivity by binding to the pathogen and blocking the molecules needed for cell entry.
Basically they sort of handcuff the viruses and subsequently disposes of them. Also they may flag them for the immune system to help dispose of them. Neutralizing antibodies are important components of vaccines and antitoxins.
Not all antibodies that bind a pathogenic particle are neutralizing. Non-neutralizing antibodies, or binding antibodies, stick to the pathogen, but do not interfere with their infectivity. That might be because they do not bind to the right region. Non-neutralizing antibodies can be important to flag the particle for immune cells, signaling them the pathogen as a target, after which the pathogen that is flagged/ targeted is processed and consequently destroyed by recruited immune cells.
Basically they do not have handcuffs, but they point towards the virus, calling the immune system to dispose of them, instead of doing it themselves.
In some cases, non-neutralizing antibodies or insufficient amounts of neutralizing antibodies that bind to virus particles can be utilized by some virus species to facilitate uptake into their host cells.
Basically the virus have become smarter, and used the same handcuffs or signals to further themselves into the host. This is Antibody-dependent Enhancement.
In a way it can be said that the antibodies indirectly “helped” the virus. This results to a worse version of the disease when getting another infection.
Dengue’s Antibody Dependent Enhancement
There are many viral borne diseases that utilize Antibody-dependent Enhancement, as it has also been observed in HIV and coronaviruses. Their ways of utilizing it is different though.
According to the World Health Organization, dengue infections are caused by four closely related viruses named DEN-1, DEN-2, DEN-3, and DEN-4. These four viruses are called serotypes because each has different interactions with the antibodies in human blood serum.
Dengue’s Antibody Dependent Enhancement
There are many viral borne diseases that utilize Antibody-dependent Enhancement, as it has also been observed in HIV and coronaviruses.
Their ways of utilizing it is different though.
According to the World Health Organization, Dengue infections are caused by four closely related viruses named DEN-1, DEN-2, DEN-3, and DEN-4.
These four viruses are called serotypes because each has different interactions with the antibodies in human blood serum.
The immunopathology of severe dengue remains incompletely understood. Most patients who develop severe dengue have had prior infection with one or more dengue serotypes.
When an individual is infected with another serotype and produces low levels of non-neutralizing antibodies they have been proposed to fail in neutralizing the virus and instead form an antigen-antibody complex – creating novel ways to escape or even use the immune system which results in the increased viral entry to the body.
The effects of dengue infection i.e dehydration or fluid overload, can be attributed to the immune system’s processes in releasing vasoactive mediators that increase vascular permeability, leading to vascular leakage, hypovolemia, and shock – these seem to be increased in a secondary infection with a different serotype. 2010 studies by Dejnirattisai W and co-authors on Dengue’s ability for Antibody-dependent enhancement published in Medline even suggested that Infants born to mothers who have had dengue are also thought to be at risk for enhanced disease.
Question: Can previous Dengue Infection Make you more susceptible to Dengue or Immune to Dengue?
Verdict: Again, while the mechanism is incompletely understood, it is known that in humans, recovery from infection by one dengue virus serotype provides lifelong immunity against that particular virus serotype. However, this immunity confers only partial and transient protection against subsequent infection by the other three serotypes of the virus. Evidence points to the fact that sequential infection increases the risk of developing severe dengue.
Prior Dengue infection technically cannot make one more susceptible to a Dengue virus of another serotype, but you are not immune to that different serotype either because the antibodies gained from one serotype only provide partial immunity to the other serotypes. Instead if a Dengue virus of another serotype unfortunately infects a human cured of dengue of a different serotupe, the illness will be more dramatic and severe than the previous one due to Dengue’s Antibody-Dependent Enhancement.
According to the European Centers for Disease Control, since there are 4 known Dengue serotypes, then theoretically, a human being may be infected with Dengue four times each more severe and dramatic than the last – and never again.
This now begs the question on how effective the Dengvaxia vaccine is which erupted as a controversy in the Philippines but surprisingly, nowhere else in the world. The problem was an alleged mishandling (including corruption) and misunderstanding on how Antibody dependent Enhancement works as it is recommended that the vaccine is only for those who have prior Dengue infections (known as seropositives) but mass vaccinations included those who had no prior Dengue infections (seronegatives) and the fear of Antibody-dependent Enhancement was politicized instead of tackled in a public health perspective – leading to a decline of vaccinations and the 2019 measles outbreak in the country.