Are we on the road to an HIV vaccine? #WorldAidsDay2014




*In 2009 an HIV vaccine trial
in Thailand to offered
glimmers of hope for a
future vaccine.

*A modified form of the
vaccine is set to be trialled
in South Africa from January

*Broadly neutralizing
antibodies could offer
another avenue against the
range of HIV viruses.

*Protective levels of 50%
would have an impact
public health.

“It only takes one virus to
get through for a person to be
infected,” explains Dr John Mascola.

This is true of any viral infection but
in this instance, Mascola is referring
to HIV and his ongoing efforts to
develop a vaccine against the virus.

“It’s been so difficult to make an
HIV/AIDS vaccine.”
Those were the words of many
working in the field of HIV vaccine
development until the results of a
2009 trial in Thailand surprised
everyone. “The field is energized,”
says Mascola, who is director of the
Vaccine Research Center at the
National Institute of Allergy and
Infectious Diseases (NIAID), as he
describes the change in atmosphere
among the vaccine community.

The trial included over 16,000
volunteers and was the largest
clinical trial ever conducted for a
vaccine against HIV. It was also the
first to show any protection at all
against infection. Two previously
developed vaccines, known as ALVAC-
HIV and AIDSVAX, were used in
combination, with the first priming
an immune response against HIV
and the second used as a booster
once the immunity waned. The duo
reduced the risk of contracting HIV
by 31.2% — a modest reduction, but
it was a start.

To date, only four vaccines have
made it as far as testing for efficacy
to identify their levels of protection
against HIV. Only this one showed
any protection. “That trial was
pivotal,” says Mascola. “Prior to that
it wasn’t known whether a vaccine
could be possible.”
In recent years there
have been parallel
findings of an equally
pivotal nature in the
field of HIV prevention,
including the discovery
that people regularly
taking their
antiretroviral treatment
(ART) reduce their
chances of spreading HIV by 96%,
and that males who are circumcised
reduce their risk of becoming
infected heterosexually by
approximately 60%.
Both improved access to ART and
campaigns to increase male
circumcision in high-risk populations
have taken place since the
discoveries and although numbers of
new infections are falling, they’re
not falling fast enough.
In 2013, there were 35 million
people estimated to be living with
HIV globally. There were still 2.1
million new infections in 2013 and
for every person who began
treatment for HIV last year, 1.3
people were newly infected with the
lifelong virus, according to UNAIDS.

A vaccine remains essential to
control the epidemic.
A complex beast
Scientists like Mascola have
dedicated their careers to finding a
vaccine and their road has been
tough due to the inherently
complicated nature of the virus, its
aptitude for mutating and changing
constantly to evade immune attack,
and its ability attack the very
immune cells that should block it.

There are nine subtypes of HIV
circulating in different populations
around the world, according to the
World Health Organization, and once
inside the body the virus can
change continuously. “Within an
individual you have millions of
variants,” explains Dr Wayne Koff,
chief scientific adviser for the
International AIDS Vaccine Alliance

HIV invades the body by attaching
to, and killing, CD4 cells in the
immune system. These cells are
needed to send signals for other
cells to generate antibodies against
viruses such as HIV and destroying
those enables HIV to cause chronic
lifelong infections in those affected.

Measles, polio, tetanus, whooping
cough — to name a few — all have
vaccines readily available to protect
from their potentially fatal
infections. But their biology is
seemingly simple in comparison with
HIV. “For the older ones you identify
the virus, either inactivate it or
weaken it, and inject it,” says Koff.
“You trick the body into thinking it
is infected with the actual virus and
when you’re exposed you mount a
robust immune response.” This is
the premise of all vaccines, but the
changeability of HIV means the
target is constantly changing. A new
route is needed and the true biology
of the virus needs to be understood.

“In the case of HIV, the old
empirical approach isn’t going to
work,” says Koff.

Scientists working on this have now
identified conserved regions of the
virus which don’t change as readily,
making them prime targets for attack
by antibodies. When the success of
the Thai trial was studied deep
down at the molecular level, the
protection seemed to come down to
attacking some of these conserved
regions. Now it’s time to step it up.

In January 2015, the
mild success in Thailand
will be applied in South
Africa, where over 19% of
the adult population are
living with HIV. The
country is second only to
bordering Swaziland for
having the highest rates of HIV in
the world. “The Thai vaccine was
made for strains (of HIV) circulating
in Thailand,” says Dr. Larry Corey,
principal investigator for the HIV
Vaccine Trials Network (HVTN), which
is leading the next trial in South
Africa. The strain, or subtype, in this
case was subtype B. “For South
Africa we’ve formed a strain with
common features to (that) circulating
in the population.” This region of
the world has subtype C.

An additional component, known as
an adjuvant, is also being added to
the mix to stimulate a stronger and
hopefully longer-lasting level of
immunity. “We know durability in
the Thai trial waned,” says Corey. If
safety trials go well in 2015, larger
trials for the protective effect will
take place the following year. An
ideal vaccine would provide lifelong
protection, or at least for a decade,
as with the Yellow Fever vaccine.

A broad attack
The excitement now reinvigorating
researchers stems not only from a
modestly successful trial, but also
from recent successes in the lab,
and even from HIV patients
themselves. Some people with HIV
naturally produce antibodies that
are effective in attacking the HIV
virus in many of its forms. Given the
great variability of HIV, any means of
attacking these conserved parts of
the virus will be treasured and the
newfound gold comes in the form of
these immune cells — known as
“broadly neutralizing antibodies.”
Scientists including Koff set out to
identify these antibodies and
discover whether they bind to the
outer coat of the virus.

The outer envelope, or protein coat,
of HIV is what the virus uses to
attach to, and enter, cells inside the
body. These same coat proteins are
what vaccine developers would like
our antibodies to attack, in order to
prevent the virus from entering our
cells. “Broadly neutralizing
antibodies” could hold the key
because, as their name suggests,
they have a broad remit and can
attack many subtypes of HIV. “We
will have found the Achilles heel of
HIV,” says Koff.

Out of 1,800 people infected with
HIV, Koff and his team found that
10% formed any of these antibodies
and just 1% had extremely broad
and potent antibodies against HIV.
“We called them the elite
neutralizers,” he says of the latter
group. The problem, however, is that
these antibodies form too late, when
people are already infected. In fact
they usually only form a while after
infection. The goal for vaccine teams
is to get the body making these
ahead of infection. “We want the
antibodies in advance of exposure to
HIV,” explains Koff. The way to do
this goes back to basics — tricking
the body into thinking it is infected.

“We can start to make vaccines that
are very close mimics of the virus
itself,” says Mascola. Teams at his
research center have gained detailed
insight into the structure of HIV in
recent years, particularly the outer
coat, where all the action takes
place. Synthesizing just the outer
coat of a virus in the lab and
injecting this into humans as a
vaccine could “cause enough of an
immune response against a range of
types of HIV,” says Mascola. The
vaccine would not contain the virus
itself, or any of its genetic material,
meaning those receiving it have no
risk of contracting HIV. But for now,
this new area remains just that —
new. “We need results in humans,”
says Mascola.

Rounds of development, safety
testing and then formal testing in
high-risk populations are needed
but if it goes well, “in 10 years there
could be a first-generation vaccine.”
If improved protection is seen in
South Africa, a first generation
vaccine could be with us sooner.
Making an Impact
When creating vaccines, the desired
level of protection is usually 80 to
90%. But the high burden of HIV
and potentially beneficial impact of
lower levels of protection warrant
licensing at a lower percentage.
“Over 50% is worth licensing from a
public health perspective,” says Koff,
meaning despite less shielding from
any contact with the HIV virus, even
a partially effective vaccine would
save many lives over time.
The next generations thereafter will
incorporate further advancements,
such as neutralizing antibodies, to
try to increase protection up to the
80 or 90% desired.

“That’s the history of vaccine
research; you develop it over time,”
says Corey. He has worked in the
field for over 25 years and has felt
the struggle. “I didn’t think it would
be this long or this hard … but it’s
been interesting,” he ponders. But
there is light at the end of tunnel.

“There has been no virus controlled
without a vaccine,” he concludes
when explaining why, despite ARVs,
circumcision, and increased
awareness, the need for a one-off
intervention like a vaccine remains
strong. “Most people that transmit it
don’t even know they have it,” he
says. “To get that epidemic, to say
you’ve controlled it, requires




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