It only survives a few weeks in the human body, but it saves your life countless times

When getting vaccinated, we may overlook that it is not the vaccine that provides protection, but the immune system
in the body.
A clear syringe punctures the skin and injects the vaccine into the muscle or bloodstream, usually taking only a few seconds
.
In the following period, and even throughout life, people are protected from many pathogens, and the key reason is that the small act of injecting vaccines activates the acquired immune system
in the human body.

Vaccines may be the first way humans think of to subdue powerful pathogens by regulating the immune system in the human body - using inactivated viruses (not toxic) or the antigenic part of the virus (usually proteins) to allow the body's immune system to rehearse in advance; When the really threatening virus comes, because the human body is familiar with them, it can quickly produce a large number of immune cells and antibodies to eliminate
pathogens.
This method has been tried and tried, and we have eliminated smallpox, and curbed polio, cervicitis, hepatitis B, measles, rabies, and more
.

Vaccines are not available?

Many times, vaccines are effective against the virus, but there are times when they hit a wall, such as HIV
.
Scientists have spent decades developing an HIV vaccine, but have never received a vaccine that actually works
.
One of the key challenges is that HIV antigens, also known as triplets, are not only complex, but also have a layer of camouflage—covered with a layer of sugar molecules
.

We can think of the structure of HIV antigens and sugar molecules as an extremely difficult mechanism
to decipher.
Antiretroviral drugs commonly used by people living with HIV are a bit like keys to crack this mechanism from the inside; If you want to use vaccines to prevent HIV infection, you need to crack the organ from the
outside by stimulating antibodies.
When scientists develop vaccines, they must fully understand the structure
.
On the surface of HIV, sugar molecules are constantly moving, obscuring some of the more conserved structures on the HIV antigen, where they are not covered, and are highly variable
.
Taken as a whole, antigens change and circulate
between different conformations.
That's
complicated enough.

Image credit: Pixabay

In addition, the genome of HIV is RNA, which is inherently highly variable
.
If the antigen-expressing gene inside HIV is mutated, the entire antigen changes and begins to cycle
in a completely new conformation.
It is precisely because of this special way of changing that HIV can quickly establish lifelong infection in the human body, which is almost impossible to completely remove
.

Antigen changes are the most important reason why viruses escape immune responses and vaccines fail.

After the antigen changes, the immune response previously activated by the vaccine will also fail, and the original antibody cannot bind to the new virus, and it will not be able to cope with the powerful blow caused by the virus
.

However, the long evolution has also given our immune system a way to
deal with it.
Over the years, a team led by Professor Shane Crotty of the La Jolla Institute for Immunology (LJI) has tried to change current vaccination methods, stimulating the immune response in animals to produce the most powerful immune attack
against HIV to date.

These findings laid the foundation for the subsequent development of a truly effective HIV vaccine, from which we can also regain the power
of our own immune system.
The two most critical studies were published in Cell in 2019 and more recently in the journal Nature
.

The immune system really can

Professor Shane Crotty and colleagues focused on B cells in the immune system, which are only a few microns in diameter but undoubtedly one of the most powerful weapons in the human body (the other being T cells).

B cells are produced by bone marrow and are still relatively young when they initially enter the blood and lymphatic system from the bone marrow, and are called "Naive B cells
.
"

They target secondary lymphoid organs, such as lymph nodes, spleen, tonsils, etc
.
These organs are distributed in many areas of the body, and their main task is to mature the "primary B cells" into a powerful immune weapon
.

The maturation process is painful, and this can be especially true
for primary B cells.
Once at their destination, they need to enter a special vesicle structure called the Germinal Center
.
This "center" contains the "dark area" and the "light area"
.
In terms of process, B cells need to stay in the "dark area" for a period of time before entering the "light area"
.
This process may also be forced, because primary B cells usually live only a few days and have a chance
to continue their life when they reach the germinal center.

After entering the "dark zone", the primary B cell is renamed "centroblasts", where it will begin to proliferate exponentially and mutate rapidly (about once every 4~6 hours) - that is, rapid evolution
.
As for whether the evolution is qualified, it is necessary to go to the "light zone" to be assessed
.
Once stimulated, they enter the "light zone" and become centrocyte
.
At this point, the cells looked embarrassed: the shape was irregular, and the nucleolus was cracked, but the effort eventually paid for some results, that is, the cell surface was filled with highly mutated B cell receptors
.

At this time, these central cells are greeted in the "light zone" by T vesicle helper cells and dendritic cells
carrying pathogen antigens.
If the receptors on the surface of the central cell bind well to the antigen, they are rewarded with a signal stimulus
to continue to live.
Subsequently, the central cells will further differentiate into secreted antibodies, killer effector B cells (plasma cells), or as memory cells for subsequent use, until this time B cells are truly mature and can go to the hair center to perform immune work in the blood system
.
However, there are not many such cells, and if other cells are lucky enough to get a survival signal, they can be rebuilt, and the rest can only be forced to die
.

Whenever a new pathogen invades or a vaccine enters the body, the immune system undergoes such a process, and B cells keep mutating until we can produce the right antibodies and use these antibodies to extinguish the pathogen, and we are safe
.
If another variant were to invade, the antibodies produced by the effector B cells and memory cells would no longer be effective
.
At this time, the germinal center will restart and evolve more powerful effector B cells, and the way left for the "veteran" may also be apoptosis
.

This process, which produces a new generation of effector B cells
, usually takes weeks.
Professor Shane Crotty calls the germinal center "the engine of antibody evolution", saying, "It's really an evolution, the process is very efficient, and the ability of new antibodies to bind viruses has increased by 1,000 times
.
" And the germination center is like a "temporary store", as soon as the crisis passes, it will collapse and disappear
.
Generally speaking, the immune response is carried out for about 15~21 days, and the germinal center will disappear, as if some unknown signal
has been received.

Shane Crotty's idea was, since the germinal center is so powerful, can it survive a little longer, making effector B cells more powerful to fight HIV?

A little longer, better antibodies

In a 2019 study published in Cell, Crotty et al.
tried a new vaccination method in common macaques (rhesus monkey), and they adopted a new, "slow" vaccination (HIV envelope protein + some adjuvant) strategy compared to the routine one-time vaccination strategy
。 The specific method is to inject the same dose of vaccine into macaques in 7 doses over a period of 2 weeks, and the dose is increased
one after another.
This vaccination method is actually close to the process of
acute infection under natural circumstances.

They found that 2 weeks after vaccination, B cells producing neutralizing antibodies appeared
in the germinal center.
In the case of a single vaccination, the number of such B cells peaks after 7 weeks and then no longer changes
.
However, if it is slowly inoculated multiple times, after 7 weeks of completion, the number of such B cells in the germinal center will continue to rise, reaching a very high value
.
In addition, the number of T vesicle helper cells will also increase significantly, which will promote the formation of more diverse antibodies
by effector B cells.
These antibodies can bind to more sites on the antigen and have a better neutralization effect
.

In a recent study published in the journal Nature, the team designed a new set of experiments to see how long the germinal center would last, and how diverse and neutralizing the antibodies were
.
The experiment included 3 groups, the first 2 groups (A and B) were given the first and second doses of the vaccine
at weeks 0 and 10 (more than 2 months), respectively.
The timing of the second dose in group C was postponed to about 30 weeks (about 7 months).

Group A was the control group, and the first dose was given using the traditional vaccination method, that is, one shot; The first dose in both groups B and C adopts a slow vaccination strategy, that is, the dose is unchanged, and the vaccine is given 7 times in 2 weeks, and the dose is increased
sequentially.
The second dose of vaccination in all three groups was completed in
one shot.
The adjuvants added to the B/C vaccine groups made some adjustments to make the germinal center's performance more robust
.

The results confirm the results previously published in Cell, but this time the data obtained is
clearer.
Three weeks after vaccination, the number of B cells (denoted by B_GC) in germinal centers in mice reached a peak
.
However, there are significant differences in the specific number, and the ratio of B _GC to the total number of B cells in the B/C group reached 24%~33%, while the value of the A group (control group) was only 3.
5%.

And in the next 10 weeks, the value of group B/C can continue to maintain at about 20%, and the data of group A has been around
3%.