HIV Vaccine and Vaccines in HIV infection

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HIV Vaccine and Vaccines in HIV infection

• Dilemma and Precautions

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ByAmr Gohar

• MB BCh Cairo University, MSc Dermato-Venereology,
  Cairo University, DGUM Worshipful Society of
  Apothecaries of London, DDerm Royal College of
  Physicians and Surgeons of Glasgow
• Ex-Registrar in Genito-Urinary Medicine and HIV,
  St Thomas Hospital, University of London
• Ex-Dermato-Venereologist, El Haud El Marsoud
  Hospital, Cairo

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The dilemma

• Despite the passage of more than 20 years since
  the discovery of HIV, no effective vaccine has
  been found to either ameliorate the disease or to
  prevent infection .
• The overwhelming majority of infections occur in
  developing countries which in many cases lack the
  resources and infrastructure to acquire and
  deliver costly antiretroviral therapy (HAART).

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The dilemma

• There are many reasons why no such vaccine has so
  far been developed.
• Natural infection with HIV itself does not result
  in protective immunity rather, it establishes
  persistent and lifelong infection and viral
  clearance and development of resistance to
  re-infection never occur.

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The dilemma

• 2. The complex structure of the HIV envelope
  glycoprotein is inherently resistant to antibody
  attack and the virus has the capacity to evolve
  quickly in order to evade any neutralising
  antibody responses mounted by the host.

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The dilemma

• 3. The selective infection, progressive
  destruction, and impaired regeneration of CD4 T
  helper cells, and the enormous genetic diversity
  of HIV (most variable virus yet discovered) with
  its continually evolving geographical
  distribution (HIV-2 itself differs greatly from
  all HIV-1 isolates) and prevalence have proven
  problematical.

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The dilemma

• 4. The ability of HIV to evade immune
  surveillance enables it to establish a state of
  proviral latency in long-lived CD4 cells thus
  providing a persistent, yet immunologically
  invisible, reservoir of virus infection.
  Actually immunisation against an organism whose
  target is an important component of the immune
  system is very difficult.

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The dilemma

• Despite these problems, research has
  continued into developing AIDS vaccines from two
  distinct perspectives, namely prophylactic
  vaccines aimed at preventing primary infection
  and therapeutic vaccines aimed at reducing the
  rate of disease progression in HIV-infected
  patients. A June 2005 study estimates that 682
  million is spent on AIDS vaccine research
  annually

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Rhesus Macaque(Rhesus Monkey)

• Our victim

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Rhesus Monkey

• July 17th, 2007 at 507 pm
• Indian Police Looking for a Thief Monkey
• The monkey actually stole a tourists glasses in
  Varanasi, Northern India and who filed a formal
  complaint against it. It seems all this is done
  to claim travel insurance!

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Rhesus Monkey

• Rhesus monkey is the typical animal model for
  vaccine research.
• HIV-1 is closely related to the chimpanzee strain
  of SIV, designated SIV cpz
• HIV-2 is most closely related to SIV sm (Sooty
  mangabeys and African Green Monkeys )

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Rhesus Monkey

• SIV monkey strains are transmitted sexually and
  usually do NOT cause AIDS in their natural hosts
  (even with large viral loads)
• SIV strains may cause an AIDS-like immune
  deficiency known as SAIDS (simian acquired
  immunodeficiency syndrome) if they cross species
  boundaries.

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Rhesus Monkey

• Rhesus macaques are native to Asia and do NOT
  carry their own strain of SIV. So Rhesus macaques
  can develop SAIDS.
• The monkey SIV strains do NOT infect humans and
  HIV does NOT infect monkeys.
• SHIV

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The International AIDS Vaccine Initiative (IAVI)

• Concept of trials phases.
• Preclinical investigations Animal studies.
• Clinical investigations Human studies.
• Phase 1 Healthy volunteers.
• Phase 2 Patients
• Phase 3 More widespread trials. It extends up to
  the time it is released for general use (Phase
  4).
• Within the field of AIDS vaccine
  research, the decision to advance candidate
  vaccines from phase I or II to phase III efficacy
  studies is somewhat complex (no consistent
  criteria).
• For phase III studies use reduction of
  viral load or preservation of CD4 T cell counts
  for assessing vaccine efficacy rather than
  prevention alone.

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IAVI

• There is scientific progress underway in the
  search for an HIV vaccine. Presently, there are
  more than 30 clinical trials with HIV vaccine
  candidates worldwide.
• The Potential Impact of an AIDS Vaccine IAVI
  estimates that even assuming that other
  programmes for treatment and prevention have been
  scaled up an HIV vaccine could substantially
  alter the course of the AIDS pandemic and reduce
  the number of people newly infected, even if
  vaccine efficacy and population coverage levels
  are relatively low. A highly effective vaccine
  could even prevent over 70 million infections in
  fifteen years.

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IAVI

• Unless we can alter the number of people who
  become infected, the costs of treatment and care
  will mount into the tens of billions of dollars,
  even before considering rising drug resistance
  and the associated need for more expensive
  alternative drugs. Moreover, theses costs must be
  met every year for the foreseeable future.

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IAVI

• Some groups could especially benefit from an HIV
  vaccine, particularly marginalised and vulnerable
  populations.
• The challenges in reaching these underserved
  populations underline the importance of making
  investments in HIV vaccine research and
  development today.

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IAVI

• The negative effects of the AIDS pandemic are
  substantial, in terms of lives lost, human
  suffering, shattered families and communities,
  lowered economic productivity, and higher health
  care costs. A vaccine that could reduce the
  number of new infections by 20 to 80 would
  produce enormous health and economic benefits and
  could help to dramatically curtail the pandemic.

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Which approach?

• ? Live attenuated (Effective in animals but
  unsafe in humans)
• ? Subunit vaccine B cells of the immune system
  will produce antibodies against the antigen.
  Antibodies lock on to the antigen/protein of the
  pathogen. When the entire pathogen (HIV) enters
  the body, the antibodies will attach to the
  proteins on the outer shell of the pathogen,
  coating it and making it harmless, or
  neutralising it. It is so difficult to
  configure immunogens from the HIV envelope that
  effectively elicit neutralising antibody
  responses (AIDSVAX gp120 vaccine failed)

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Which approach?

• ? DNA vaccine (common strategy) 1 or some HIV
  genes enter into human cells and use the cells
  equipment to produce some protein(s) of the
  pathogen encoded by the gene(s). When the protein
  is produced, the immune system sees it as a
  foreign or harmful antigen and produces an immune
  response. The immune system remembers this
  response, which will prepare a response against
  the whole pathogen
• ? Recombinant vector vaccine (common strategy)
  Addition of a vector will allow the vaccine to be
  more effective in creating an immune response
  than a DNA vaccine alone

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Trials

• Subunit recombinant viral envelope proteins,
  notably gp120 (Why?), have been investigated as
  both prophylactic and therapeutic vaccines, but
  phase III clinical studies have proved
  disappointing.
• In one study, involving a bivalent formulation of
  recombinant gp120 proteins from HIV subtype B,
  predominant in North America and Europe (AIDSVAX
  B/B) given to 5009 subjects most of whom were
  homosexual men, no effect on the rate of HIV
  infection was found.
• In a second study in Thailand using AIDSVAX B/E,
  a related vaccine consisting of recombinant gp120
  proteins from HIV subtypes B and E predominant in
  South-East Asia, no protection against HIV
  infection was found among 2546 HIV-negative
  injection drug users.
• Despite these disappointing results, AIDSVAX B/E
  is being evaluated in a further study in Thailand
  as the booster component of a combination
  immunisation prime-boost regimen that includes an
  attenuated canarypox vector prime (ALVAC
  vCP1521). Concerns about the potential success of
  this trial have, however, been raised by a number
  of AIDS vaccine researchers and plans for a
  similar study in the USA have been cancelled due
  to poor antigenicity exhibited by the combination
  during earlier investigations.
• Garber DA, et al. Prospects for an AIDS
  vaccine three big questions, no easy answers.
  Lancet Infect Dis 2004 4 397413.

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Trials

• Monoclonal antibodies act by penetrating gp120
  and other viral envelope proteins, thereby
  preventing CD4 attachment to the virus. Since
  they have activity against a broader range of
  isolates and may be produced in relatively large
  quantities by recombinant technology, passive
  delivery of a cocktail of monoclonal antibodies
  is being investigated in animal models as a means
  of prophylaxis. The cost of this approach may,
  however, potentially prohibit its future use on a
  wide scale in humans.

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Trials

• Cytotoxic T lymphocyte (CTL) hypothesis This
  proposes that vaccination of uninfected
  individuals will not prevent infection but will
  induce an anti-HIV CTL (CD8) response. If
  subsequently infected with HIV these immunised
  persons would be better able to control viral
  replication and progress to AIDS much more slowly
  or perhaps not at all and potentially decrease
  viral transmission. The validity of this
  hypothesis is at present uncertain but it has
  been supported by the observation of low level,
  yet detectable, HIV-specific CD8 T cell
  responses in certain cohorts of highly exposed
  but uninfected individuals.
• Numerous studies are underway to assess the
  safety and immunogenicity of a number of
  replication-defective recombinant viral vectors
  (e.g. modified vaccinia Ankara strain) and also
  bacterial, yeast, and plasmid DNA vectors, all of
  which are designed to elicit antiviral CD8 T
  cell responses.

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Trials

• Recombinant plasmid DNA immunogens are also under
  investigation as potential AIDS vaccines because
  of their desirable safety profile and ability to
  express defined and discrete inserted HIV
  antigens. They are either used singly or as a
  priming immunogen in prime-boost regimens using
  different vaccine vectors for sequential
  immunisation. Initial results in preclinical
  animal studies were encouraging, but results have
  been disappointing in subsequent phase I human
  studies.

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An Ideal HIV Preventive Vaccine

• Safe does not cause any serious side effects
• Efficacious must show that people who are
  vaccinated have significantly less infections or
  disease
• Available should be able to be produced in
  large quantities and be deliverable to everyone
  who needs it

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An ideal HIV Preventive Vaccine

• 4. Effective must decrease the disease in the
  general population
• 5. Stable can last for a long time in various
  conditions or environments
• 6. Accessible should effectively reach the
  populations in need quickly and easily
• 7. Affordable should be affordable by
  governments or individuals who need it most

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New therapeutic HIV Vaccine

• GeoVax vaccine (genetically engineered smallpox
  virus). The main reason for using the smallpox
  virus is that it is one of the most powerful
  stimulators of immunity known to man. And it
  seems that when the virus carries HIV genes,
  those powerful immune responses transfer to HIV
  as well. A side benefit of the GeoVax vaccine is
  that recipients will become immune to smallpox,
  should that virus return via bioterrorist attack
  or lab accident!
• MRKAD5 (suspended)

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Who develops HIV vaccine ad for whom?

• A Vaccine developed in Great Britain for
• example against the locally prevalent HIV-
• 1 isolates will be totally ineffective in other
• parts of the world where other subtypes
• predominate.

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Controversy of the new HPV Vaccine and its
implication

• Its effect on sexual activity.
• It can be given starting from 9 years of age!
• Effect of HIV Vaccine on sexual activity.

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Warning

• HIV-positive patients should NOT receive
• the following vaccines
• BCG
• Typhoid (oral)
• Yellow fever
• HIV-positive patients with or without symptoms
  can receive the following live attenuated
  vaccines MMR and varicella-zoster (but not
  whilst severely immunosuppressed(. Use of normal
  immunoglobulin should be considered after
  exposure to measles and varicellazoster
  immunoglobulin considered after exposure to
  chickenpox or herpes zoster. HIV-positive
  individuals with or without symptoms can receive
  the following inactivated vaccines cholera
  (oral), diphtheria, haemophilus influenza type b,
  hepatitis A, hepatitis B, influenza,
  meningococcal, pertussis, pneumococcal,
  poliomyelitis (injection), rabies, tetanus,
  tick-borne encephalitis, typhoid (injection).
• Joint Formulary Committee. British
  National Formulary 54ed. London British Medical
  Association and Royal Pharmaceutical Society of
  Great Britain 2007