April 10 2020
pas·sage
noun
the act or process of moving through, under, over, or past something on the way from one place to another.
Serial passage refers to the process of growing bacteria or a virus in iterations.
Clinically, this is the process of passage of infectious agents, including viruses, through patients.
The process includes least three steps:
Entry - virus must be able to
Settle in a new host;
Attach to host’s target cells;
Enter target cells;
Replication - viral multiplication in target cells;
Exit target cells and eventually the host himself.
All of the above must be done while avoiding and overcoming host defenses and medications, if any.
Once exited, virus must find a new host, or it will become a dormant fragment of genetic information and lose its ability to enter the next host.
An army of viruses, just as any army at war, loses its solders while storming fortress after fortress (patient after patient), soldiers themselves get weaker and weaker, and eventually must stop to regroup, recuperate and replenish supplies.
The process of serial passage leads to weakening - attenuation of viruses. One of the reasons is that viruses do not have a mechanism to assure error-free replication and accumulating mutations weaken them. At the same time, next hosts (like fortresses) prepare their defenses and eventually repel viruses (for instance by washing hands), or destroy them within while viruses are trying to overcome multiple lines of defense:
Non-specific immune response (similar to fortress walls repelling various types of attackers - from infantry to tanks);
Cell-mediated immune response including natural killers (NK cells) and other T-lymphocytes (these are like mines and anti-tank weapons); and
Humoral immune response - intruder-specific antibodies made by B-lymphocytes.
Importantly, humoral immune response takes time to develop (anywhere between few days to several weeks). This process is called seroconversion: from zero antibodies at the time of infectious agent entry (unless previously exposed or vaccinated) to abundance of antibodies (under proper immune response).
The antibodies are useful for several purposes:
Neutralizing remaining intruders, which are usually none in case of acute infections because infection is gone in two-three weeks;
Protecting the host from the next waive of same infection;
Protecting others, if collected from recovered patients and injected into a sick one;
Formation of “herd” immunity;
Documenting the fact of infection, hence much awaited antibody tests for SARS-CoV-2;
The serial passage and mechanisms of cellular and humoral immune response are used to make vaccines, in particular attenuated (weakened) vaccines.
The technique of serial passage has been around since the 1800s. In particular, Louis Pasteur’s work with the rabies vaccine in the late 1800s exemplifies this method.
Pasteur created several vaccines over the course of his lifetime. His work prior to rabies involved virus attenuation, but not through serial passage. In particular, Pasteur worked with cholera and found that if he cultured bacteria for long periods of time, he could create an effective vaccine.
One way to attenuate a virus to a host is by passing the virus in different species. The idea is that, as a strain of a virus becomes more adapted to a different species, the strain will become less adapted to the original host, thus decreasing in virulence with respect to the original host. This is the implicit principle that Louis Pasteur was unknowingly making use of when he passed the rabies virus in monkeys and ended up with a virus that was less dangerous to dogs, for example.
The above process is effective under one obligatory condition: immunocompetence of hosts.
Conclusion: the process of serial passage leading to attenuation of infectious agent (such as virus) in immunocompetent hosts inevitably ends epidemic regardless of its origins, virulence, etc.
Rephrasing for epidemiology buffs: the process of serial passage leading to attenuation of infectious agent (such as virus) in immunocompetent hosts inevitably ends epidemic by bringing R0 (“R naught”) - the reproduction number to below <1.
Stay tuned for the next blog: what happens if hosts are immunocompromised and why young doctors die?