Broadly neutralizing anti-HIV antibody Viruses replicate inside cells, which shields them from some components of the immune system. In particular, antibodies can’t penetrate inside a cell1 to bind to a virus there, so antibodies are not much use for eliminating a viral infection.2 For some viruses that have to exit the cell to spread to a new target cell, antibody may help limit spread, but many viruses can spread directly from one cell to its neighbor without ever being exposed to antibodies. So once a virus has entered a host’s cells, you probably want mostly cell-mediated immune responses, such as T helper cells and cytotoxic T lymphocytes, to get rid of the virus.

That’s for eliminating viral infections. What antibodies are often extremely good at is blocking infections–stopping the virus from ever getting a foothold. A virus that enters your body has to be exposed to extracellular components at least briefly before it can burrow into its protective cell. During that phase the virus is vulnerable to antibody-mediated inhibition. Antibodies therefore may be relatively unhelpful for getting rid of an ongoing infection, but they can be very good at protecting against new infections.

Not surprisingly, then, most3 antiviral vaccines depend on inducing a strong and specific antibody response. That also means you can often get away with killed virus vaccines like the Salk polio vaccine, or even subunit vaccines like Hepatitis B vaccine; these are very poor at inducing cytotoxic T lymphocyte (CTL) responses, but they don’t have to. Killed vaccines are, in principle, intrinsically safer than the attenuated viruses, or even vector-based recombinant vaccines.

Why are researchers looking for alternatives?

So why is there so much interest in developing vaccines that stimulate CTL? Why are so many groups working on vector-based vaccines or attenuating viruses? One reason is that these vaccines are (again, in principle) intrinsically more immunogenic than killed vaccines. If you can give one dose of vaccine, and then have your antigens stick around for a couple of weeks, or even amplify themselves as they replicate in situ, then you may not need to give a second (booster) dose of the vaccine. That’s a moderate advantage in the first world, and potentially a huge advantage in the third world, where you may only have one chance to visit your patients.

Another reason is that to a large extent we’ve already nailed the simple problems. If a killed vaccine can protect against a major pathogen, we probably already have that vaccine up and running. We’re left with those virus diseases that, for one reason or another, are not easily prevented by antibody-type responses, and so cellular CTL-type responses are the most promising next step.

HIVWhat keeps a virus from being blocked by antibodies? There are a number of reasons, but the most obvious is that the virus offers a moving target to antibodies. HIV is probably the most famous example of this approach. The HIV surface is dominated by glycoproteins that are enormously variable; an antibody that blocks one particular HIV strain does nothing against a different strain. Hepatitis C virus (HCV) is another virus with highly variable surface proteins. Malaria, a parasite rather than a virus, has enough room in its genome to take this strategy even further. As well as using strain variation, individual parasites can dynamically change their surface proteins, stepping methodically through some 60 variants.4

Surface antigens in these pathogens have probably evolved to be variable; there’s been selective pressure for a pathogen to be different from the majority, since that way they’re less likely to infect an immune host.5 Internal antigens–those that are not exposed to antibodies-tend to be more highly conserved. Internal antigens aren’t exposed to antibodies, but they’re perfectly good targets for CTL. This is one reason for the interest in developing vaccines that induce good CTL responses.

Back to the future: Workarounds for antibody-based vaccines

There’s another approach, though. We have a lot of experience with antibody-based vaccines. It would be nice if there was a way to use them against HIV and HCV. Are there sections of the virus surface that are not variable? If so, then designing a vaccine that raises antibodies against these regions might be effective against many different strains. That’s been a hot topic for quite a while, and in fact there have been some steps forward on this front for HIV.6 More recently, in the latest issue of Nature Medicine7 there’s an article suggesting that some antibodies may be able to neutralize many hepatitis C strains.

The results provide evidence that broadly neutralizing antibodies to HCV protect against heterologous viral infection and suggest that a prophylactic vaccine against HCV may be achievable.

  1. Yes, I know that some forms of antibody routinely penetrate cells as they’re pumped into the gut, for example, but let’s stay relevant.[]
  2. Perhaps antibodies are important in some cases for triggering antibody-dependent cell-mediated cytotoxicity (ADCC) by NK cells, but again let’s not get sidetracked.[]
  3. If not all. I can’t think of a counterexample offhand[]
  4. Developmental selection of var gene expression in Plasmodium falciparum. Qijun Chen, Victor Fernandez, Annika Sundstram, Martha Schlichtherle, Santanu Datta, Per Hagblom & Mats Wahlgren. Nature 394, 392-395 (23 July 1998) []
  5. That being said, I don’t know that this has been formally shown for any of these agents; and in fact the only study I know of off the top of my head specifically did not find evidence for frequency-dependent selection in malaria surface protein alleles: Sequence Variation in the T-Cell Epitopes of the Plasmodium falciparum Circumsporozoite Protein among Field Isolates Is Temporally Stable: a 5-Year Longitudinal Study in Southern Vietnam. Amadu Jalloh, Huynh van Thien, Marcelo U. Ferreira, Jun Ohashi, Hiroyuki Matsuoka, Toshio Kanbe, Akihiko Kikuchi, and Fumihiko Kawamoto. Journal of Clinical Microbiology, April 2006, p. 1229-1235, Vol. 44, No. 4  []
  6. For example, Structural definition of a conserved neutralization epitope on HIV-1 gp120. Tongqing Zhou, Ling Xu, Barna Dey, Ann J. Hessell, Donald Van Ryk, Shi-Hua Xiang, Xinzhen Yang, Mei-Yun Zhang, Michael B. Zwick, James Arthos, Dennis R. Burton, Dimiter S. Dimitrov, Joseph Sodroski, Richard Wyatt, Gary J. Nabel & Peter D. Kwong. Nature 445, 732-737 (15 February 2007)–the source of the image at top here[]
  7. Broadly neutralizing antibodies protect against hepatitis C virus quasispecies challenge. Mansun Law, Toshiaki Maruyama, Jamie Lewis, Erick Giang, Alexander W Tarr, Zania Stamataki, Pablo Gastaminza, Francis V Chisari, Ian M Jones, Robert I Fox, Jonathan K Ball, Jane A McKeating, Norman M Kneteman & Dennis R Burton. Nature Medicine Published online: 6 December 2007  []