Broadly neutralizing anti-HIV antibody
Broadly neutralizing anti-HIV antibody
in contact with HIV gp120

My research is focused on T cell responses to viruses, so I don’t tend to talk about antibodies all that much here. For that matter, I personally don’t find antibodies very interesting, research-wise. But I don’t want to dis antibodies as clinical entities, and a few recent papers emphasize how useful they can be. (See also my previous post, Antibody-based vaccines)

Very brief background: Antibodies (also known as immunoglobulins) and T cells are the two branches of the adaptive immune response. The adaptive immune response, invented by sharks1 is capable of a broad, flexible, and long-lasting response to pathogens, contrasting to the relatively narrow and inflexible innate immune response. The T cell response involves cells as the effectors; the antibody response involves (surprise!) antibodies, which are simple proteins, usually soluble — that is, floating freely around in the blood or in various bodily secretions. Antibodies can neutralize pathogens in various ways, almost all of which require the antibody to physically bind to the pathogen. That means that the target on the pathogen has to be exposed (on the outside of the pathogen) where the antibody can see it. It also requires the target on the pathogen to be moderately constant; if antibodies target a particular molecule on a pathogen, and that molecule changes later on, then the pathogen is potentially invisible to the antibody.

Almost all vaccines work mainly through antibodies. Antibodies are relatively easy to induce in a relatively predictable way, whereas even today it’s harder to consistently and reliably induce a protective T cell response to a pathogen. Dead pathogens can induce antibodies, but not T cells (without a lot of jiggering); even pieces of pathogens — subunit vaccines — can induce strong antibody responses; so you can have a big safety factor built in to antibody-based vaccines.

So if antibodies worked for polio and measles and pertussis and so many other highly-effective vaccines, why is there any interest at all in T-cell based vaccines? Simply put, it’s because we’ve already nailed the easy targets for vaccines, and the ones that are left are hard because in general antibody-based vaccines haven’t worked well against them. The 800-pound gorillas out there are malaria and HIV, and antibody-based vaccines against malaria and HIV (and a universal influenza vaccine, the other 800-pound gorilla) simply haven’t been effective. The conclusion has been that effective vaccines against these guys will require T cells.

Anti-lysozyme antibody contacting lysozyme
Anti-lysozyme antibody contacting lysozyme

But that’s not necessarily so. Some papers I’ve run across recently demonstrate that antibodies are more versatile and effective than I usually give them credit for. First, there the observation2 that antibodies actually can protect against HIV. The key seems to be driving constant production of the antibody — in one case,3 via gene therapy rather than conventional immunization. This points to a solution to one of the major problems facing anti-HIV antibodies, but not the second: the constant mutation and variation of HIV surface proteins means that antibodies are usually limited to targeting a very limited number of HIV strains — there’s little cross-protection between strains, in other words. But there’s also some encouraging work on that front, with the identification of broadly cross-reactively neutralizing antibodies. 4 I’ve had questions about how you’d make use of such an antibody — constructing a vaccine that could reliably drive production of this precise antibody would be difficult — but the gene therapy approach would circumvent that problem altogether, so it might kill two birds with one stone.

Malaria vaccines have been under development for decades and none have worked very well. The ones in clinical trials (I’ve talked about them here and here) offer maybe 50% protection — a hell of a lot better than nothing, but as vaccines go pretty awful. A complementary approach to preventing disease in malaria-exposed people — the aim of these sorts of vaccines — would be to reduce spread of the parasite from one infected person to another individual; if this worked, then the disease frequency would, hopefully, drop. 5 I was impressed to see a paper6 describing an antibody-based approach to blocking malaria transmission. The key here seems to be a fairly simple approach (simple in concept, not in practice) of optimizing production of the vaccine target.

As we all know, influenza vaccines have to be tweaked every year, because the vaccines only protect against the very specific strains within the vaccine itself.  (See also this post and this one.)  The problem is similar to HIV — influenza virus surface proteins are highly variable, and antibodies against one strain don’t cross-react against different strains. There’s a lot of interest in develop T-cell-based vaccines with a broader cross-reactivity, but in the meantime there’s some evidence that it might be possible to do something similar using antibodies. There are several papers showing broadly cross-reactive antibodies — for example:

Here we describe a panel of 13 monoclonal antibodies (mAbs) recovered from combinatorial display libraries that were constructed from human IgM+ memory B cells of recent (seasonal) influenza vaccinees. The mAbs have broad heterosubtypic neutralizing activity against antigenically diverse H1, H2, H5, H6, H8 and H9 influenza subtypes. Restriction to variable heavy chain gene IGHV1-69 in the high affinity mAb panel was associated with binding to a conserved hydrophobic pocket in the stem domain of HA. The most potent antibody (CR6261) was protective in mice when given before and after lethal H5N1 or H1N1 challenge. 7

Again, there are technical difficulties — how to drive an immune response against such a precise target, given that it doesn’t arise with any significant frequency in natural infections or with conventional vaccines — but just knowing that the potential is there, is intriguing.

Does this mean we should abandon T-cell approaches and return to tried-and-true antibodies?  I don’t think so; most likely the most effective immunity will be a combination of antibodies and T cells, as happens in natural infections, and in each of these cases the work is extremely preliminary.  But on the other hand, we shouldn’t lose track of the antibodies (boring though they are) in the rush to T cells.

  1. And, in quite a different form, by lampreys and hagfish[]
  2. Reviewed in Haigwood, N., & Hirsch, V. (2009). Blocking and tackling HIV Nature Medicine, 15 (8), 841-842 DOI: 10.1038/nm0809-841[]
  3. Johnson, P., Schnepp, B., Zhang, J., Connell, M., Greene, S., Yuste, E., Desrosiers, R., & Reed Clark, K. (2009). Vector-mediated gene transfer engenders long-lived neutralizing activity and protection against SIV infection in monkeys Nature Medicine, 15 (8), 901-906 DOI: 10.1038/nm.1967[]
  4. For example, see this paper and references therein: JULIEN, J., BRYSON, S., NIEVA, J., & PAI, E. (2008). Structural Details of HIV-1 Recognition by the Broadly Neutralizing Monoclonal Antibody 2F5: Epitope Conformation, Antigen-Recognition Loop Mobility, and Anion-Binding Site Journal of Molecular Biology, 384 (2), 377-392 DOI: 10.1016/j.jmb.2008.09.024 []
  5. I think this has been modeled in a paper I saw a while ago, but I don’t remember the details of the model.[]
  6. Chowdhury, D., Angov, E., Kariuki, T., & Kumar, N. (2009). A Potent Malaria Transmission Blocking Vaccine Based on Codon Harmonized Full Length Pfs48/45 Expressed in Escherichia coli PLoS ONE, 4 (7) DOI: 10.1371/journal.pone.0006352[]
  7. Throsby, M., van den Brink, E., Jongeneelen, M., Poon, L., Alard, P., Cornelissen, L., Bakker, A., Cox, F., van Deventer, E., Guan, Y., Cinatl, J., Meulen, J., Lasters, I., Carsetti, R., Peiris, M., de Kruif, J., & Goudsmit, J. (2008). Heterosubtypic Neutralizing Monoclonal Antibodies Cross-Protective against H5N1 and H1N1 Recovered from Human IgM+ Memory B Cells PLoS ONE, 3 (12) DOI: 10.1371/journal.pone.0003942[]