comment: the quest for an hiv vaccine

“ever tried. ever failed. no matter. try again. fail again. fail better.”

samuel beckett, worstward ho

the problem

the old adage that ‘prevention is better than cure’ still holds for human health. for hiv, there are several approaches to prevention, such as condoms and the use of drugs originally developed to treat hiv infection for pre-exposure prophylaxis, discussed in this issue of microbiology today by noel gill. however, unlike antiretroviral drugs, vaccines should not require healthy ‘at risk’ individuals to take them for life. vaccines are our ‘weapons of mass protection’ with the eradication of smallpox and the huge reduction of yellow fever, polio, measles and cervical cancer to name a few viral diseases. so why don’t we have an efficacious hiv vaccine, 35 years after the discovery of the virus?

with 1.5 million new infections by hiv each year, this failure is not due to want of effort by researchers, pharma and funding agencies. one major problem is the enormous genetic and antigenic variability of hiv strains across the world. it is like having to cope with 1,000 strains of influenza virus all at once – and we know how difficult it is for the world health organization to make the right call each year for seasonal ’flu vaccines. a second problem is that the surface of hiv particle has a ‘glycan shield’ that blocks potentially protective antibodies from reaching their targets. a third point is that hiv is a chronic, persistent infection that targets the cd4 lymphocytes of the immune system itself (as well as macrophages). moreover, the virus inserts its genome into our own dna, so that once infection has become established it is a formidable problem to eliminate it.

the vaccines that have been developed since edward jenner’s smallpox vaccine 220 years ago generally mimic the body’s own immune response to infection. they act by preventing infection through antibodies with an immunological memory, supplemented by cellular immunity to clear up the pockets of virus-infected cells that might become established if ‘sterilising’ protection cannot be achieved. this doesn’t work for hiv. as josé esparza, former head of hiv immunity at the bill & melinda gates foundation, pointed out, we need to ‘do better than nature’.

 

antibody immunity

despite these daunting problems, i feel less despondent about the ultimate success of hiv vaccine development than i did 10 years ago. monoclonal antibodies (mabs) have been isolated from a small proportion of hiv-positive people which are both potent and neutralise almost all strains of hiv of different subtypes. they target conserved sites on the virus envelope; for instance, all hiv strains bind to the cd4 receptor on t-cells and thus antibodies that block receptor interaction prevent the initiation of infection. other potent and broadly neutralising antibodies recognise epitopes on the viral surface which include the glycan structures that otherwise prevent access, providing a sort of achilles heel on the virus. these mabs have been exploited to select recombinant antigens composed of hiv trimeric glycoproteins that maintain their native state. if used as immunogens, they ought to elicit a polyclonal humoral immune response with similar potency and breadth. unfortunately, most immunisation tests to date resulted only in strain-specific neutralisation, yet improvements to immune responses using better immunogens and adjuvants are in the pipeline.

the potent, broadly neutralising mabs are also being exploited in passive immunity; they can act as a form of pre-exposure or immediate post-exposure protection. this is reminiscent of the administration of anti-toxin to diphtheria (for which emil von behring won the first nobel prize in medicine in 1901), and of post-exposure protection against rabies – but uses 21st century technology to deliver sufficient levels of mab.

cellular immunity

for cell-mediated immunity, vaccine design has focused on internal proteins of the virus, especially the major core antigen, p24. again, hiv variation is a problem but this has been approached by analysing viral peptides that bind to the major histocompatibility antigens most frequent in the human population and modifying p24 to include them. bioinformatics has helped to design ‘conserved’ and ‘mosaic’ immunogens to elicit broadly protective t-cell responses to candidate vaccines. such immunogens are being tested pre-clinically in non-human primate studies and in clinical trials expressed by viral vectors including adenovirus, modified vaccinia virus and human cytomegalovirus. clinical trials have shown moderately promising results. however, we should beware of premature optimism and hype when protection is claimed at, say, a 30% level, but the statistical confidence limits also encompass a possible null result. complete protection through vaccination alone is unlikely to be achieved for hiv, but even a partially efficacious vaccine could be included as a component of our prevention strategy.

further reading

barouch, d. h. & others (2018). evaluation of a mosaic hiv-1 vaccine in a multicentre, randomised, double-blind, placebo-controlled, phase 1/2a clinical trial (approach) and in rhesus monkeys (nhp 13-19). the lancet 392, 232–243. doi:10.1016/s0140-6736(18)31364-3

brady j. m., baltimore, d. & balazs, a. b. (2017). antibody gene transfer with adeno-associated viral vectors as a method for hiv prevention. immunol rev 275, 324–333. doi:10.1111/imr.12478

corey, l. & others. (2015). immune correlates of vaccine protection against hiv-1 acquisition: a review. sci transl med 7, 310rv7. doi:10.1126/scitranslmed.aac7732

mccoy, l. e. & burton, d. r. (2017). identification and specificity of broadly neutralizing antibodies against hiv. immunol rev 275, 11–20. doi:10.1111/imr.12484

ndung’u, t. & weiss, r. a. (2012). on hiv diversity. aids 26, 1255–1260.

robin weiss

division of infection & immunity, university college london, wc1e 6bt, uk

[email protected]

robin weiss frs is emeritus professor of viral oncology at university college london. he has been a member of the 英格兰vs美国谁会赢？ for 50 years and was president 2006–2009.

what advice would you give someone starting out in this field?

(a) perseverance.

(b) choose a project that will yield publishable results of good science even if it doesn’t hit the jackpot of a successful vaccine.

what inspired you to become a microbiologist?

i slid into it by chance. i was offered a phd place by developmental biologist michael abercrombie to study cell transformation induced by rous sarcoma virus and gradually became as interested in viruses as in the cancers they caused. then, with the onset of aids, i became interested in epidemics. now, in retirement, i am interested in the history of microbiology.

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image: coloured scanning electron micrograph of a t-lymphocyte blood cell (green) infected with hiv (red), causative agent of aids. nibsc/science photo library.