Vaccines are the safest, cheapest and most effective way
to protect against infectious diseases  but to make a good one remains a
challenge, and traditional approaches are now stretched to the limit while
fatal diseases, like HIV and malaria, remain without vaccine. 
 But a major breakthrough that turns vaccine design on its head has now been published in Nature on the 6th of February - a new computational method that, from the protective antibodies of patients, can design the vaccine specific to induce them (and protect against the disease).

Showing the potential of the new design  Bruno
Correia from the Instituto Gulbenkian Ciência and Instituto de
Tecnologia Química e Biológica (IQTB) in Portugal and colleagues from the
Department of Biochemistry at the University of Washington and The Scripps
Research Institute designed a vaccine for the
human-infecting respiratory
syncytial virus (RSV). The vaccine was tested in
rhesus monkeys (which have a very similar immune system to us), and proved to induce protective
antibodies. RSV was a particular good example of the vaccine potential,  because not
only it causes an often deadly respiratory infection among very young children
so it is a dangerous virus, but is also one with which scientists have
struggled to make a vaccine for a long time without success.

So how do vaccines normally
work, and why there are some more difficult to make?

Nature is full of disease-inducing agents, like
viruses or bacteria (collectively known as pathogens or germs) and it is easy to
get infected. If we do, our immune system (the cells and organs
that protect us against disease) mounts a protective response that, once the
pathogen is eliminated, will leave behind a protective immune memory. This
memory, if we reencounter the pathogen, can now trigger a much faster and
effective attack (called secondary
response) that eliminates the threat before disease develops. That is why often
we only have a disease once.

Vaccines work similarly, the difference being that
that first encounter is not with a live infectious pathogen, but instead with a
vaccine that contains a dead, attenuated (weaken) or partial pathogen. Without
giving disease these are enough, nevertheless, to create an immune memory that
protects the individual if he/she ever comes in contact with the “real thing”.

Image: Post World War II United Kingdom poster promoting vaccination against diphtheria.

But despite all vaccines already developed, some
serious diseases, in particular some by fast changing/mutating viruses, like HIV or hepatitis C, remain without
protection. The problem is that these viruses change so fast that vaccines (and
the immune memory they trigger) become obsolete very quickly. Unless that it
is, if they are against those epitopes (the parts of the pathogen
targeted by the immune system) crucial for viral survival, what means that they
cannot be changed. This is why flu vaccines only work for one year - because
the flu virus (influenza) has an extremely high mutation rate.

But even if we use the right epitopes, there is still
no certainty that a new vaccine will lead to a protective immune response. The
problem is that we still do not fully understand how the protection works - neutralizing
antibodies (antibodies capable of blocking the effects of the pathogen)
are crucial, but the rest is much less clear.
This means that at the moment vaccines are developed empirically (by
observation/experimentation), and when this fails we are stuck.

A possible solution (although so far only in theory)
are “epitope-focused vaccines”,
which turn the process backwards and use the end product – the neutralizing antibodies –to create the
vaccine that induces them.

For that it is necessary to identify the epitope
targeted by the antibody, and then construct a protein scaffold (a holding structure) to carry it just like in the virus,
to be sure to trigger the right antibody response. But despite its potential
and many attempts, until now this has not been attained

In the study now published Correia and colleagues
develop a computational program called
“Rosetta - Fold from Loops” to design new protein scaffolds that - contrary
to previous attempts - are flexible, meaning that they can be fitted around the
epitope to better mimic the natural viral site. They chose an  antibody used to treat RSV infection, that
targets a known viral epitope.As the crystal structure of the virus and the
neutralizing antibody bond together was found, this informed researchers of what
shape should the scaffold be.

Next came the hard part: to design a structure that
held the epitope, while having the right biophysical and structural
characteristics to induce the protective antibodies. 

With the
new software Correia produced 40.000 possible structures that were then
screened in the computer and a few (8) were characterized in the laboratory
until only 6 of best final designs were chosen. All the designed
epitope-scaffolds bound to the neutralizing antibody, and all had similar,
although not identical, scaffold.

But are the new constructs
clinically relevant for the disease?

To test that, the researchers looked into individual
that had the disease (so have RSV-specific antibodies), testing their sera with
the new epitope-scaffolds. Impressively several individuals had antibodies that
recognized the “new vaccines”, while none reacted to scaffolds alone

Now could these “new
vaccines” induce neutralizing antibodies?

To test for this the different “epitope-scaffolds”
formulations were injected into mice and rhesus macaques, which were
then tested for a RSV immune response. While some mice could
produce antibodies against the virus, none of their antibodies could neutralize
the virus. In contrast, after a few vaccination rounds with the new structures
the majority of the macaques were producing neutralizing antibodies what was very promising
considering the similarity between our immune systems

“Actually
the macaques were producing antibodies more potent than the prophylactic
antibody that is used to treat high risk patients, the one from where we started,” says Correia, “This when
the natural infection exposes multiple viral epitopes, while our scaffolds only
have a single epitope supposedly triggering a much more limited immune response.
The fact that the results obtained are so good proves the ability of our method to fully explore the immune
system abilities when producing therapeutic antibodies. “

What is
particularly remarkable in Correia and colleagues’ latest work is how close we
become to a real life result as Correia explains, “obviously our structures
still need to be optimized and tested in humans, but these results are the
first part of the protocol to develop a vaccine against RSV putting us in a good
position to create a cheap and effective RSV vaccine.”

This is
even more important because of RSV characteristics - a virus responsible for
about 7% of all deaths among children between 1 month and 1 year that presents
multiple challenges for vaccine design. In fact, not only RSV mutates very
fast, but even its non-live vaccines (usually the safest alternative) can not
be tested in very young children – the highest priority target population –- since clinical
trials had to be stopped because vaccinated infants went to develop a more
severe disease instead of being protected. Synthetic vaccines with just one protective
epitope,, like the one here described, should however be much safer.

These remarkable new
results prove the viability of epitope-focused and scaffold-based vaccine
design, opening the door to use these strategies on other illnesses, including
HIV. In a world where infectious diseases caused 18.5% of all human
deaths and 23% of disability-adjusted life years as recently as 2010, this is
no doubt very good news.