Colors of New Mexico

The opening was a big success, thank you all so much for coming, those who could come, and for sending wishes and good vibes, those who couldn't. The pictures will be up until October 10 at the Silver Sun Gallery at 656 Canyon Road, in Santa Fe, NM.

And here's a photo of me looking at me, taken by my friend Karen:

Vaccines: what is the meaning of phase I, II and III?

I'm often asked, "How long will it take to finally have an HIV vaccine? Are we close? What about this study that published good results on an HIV vaccine?"

Right now, the HIV community is generally optimistic that we will indeed have an HIV vaccine within the next decade. This is based on the relatively recent discovery of new broadly neutralizing antibodies and the mildly positive results obtained by one of the five major efficacy trials, the RV144 Thai trial, which found a 31% reduction in HIV acquisition in vaccinated subjects versus placebo [1].

I'm also often forwarded published papers on successful HIV vaccine trials, with the attached question: "Is it done, then?"

The answer is, "No, not yet."

As I explained in my earlier HPV vaccine post, once a vaccine is approved to be tested on humans, like all human health interventions, it has to be tested in three phase clinical trials, called phase I, II, and III.

"Clinical product development typically begins with phase I studies that evaluate the safety and biological activity of a drug, vaccine, or other intervention and proceeds ultimately to phase III efficacy trials that support licensure. [. . .] Phase II clinical trial evaluation affords an opportunity to discover less frequent side effects of the intervention and to provide better quantitation of the agent‚ activity and safety in a larger and more diverse participant population. [2]."

So, a successful phase I trial means that the vaccine is safe to use on humans and it does no harm. A phase I trial does not prove that the vaccine can protect against the disease. It can take up to a decade to go from a phase I to a phase III trial. Phase III, when successful, is what ultimately proves the vaccine's efficacy.

So far there have been many phase I HIV vaccine trials, but there only have been a handful phase III trials, of which the most successful one was RV144 with the mild 31% reduction in infection rate.

Vaccines like HPV that are now being offered to the public have undergone all three clinical trial phases. This is what I was trying to explain when I discussed the HPV vaccine and I said that despite the concerns raised by the Japanese government, the vaccine wouldn't have been FDA approved had it not passed all three phases of clinical trials that proved its safety first. For example, you can read the results of a phase I HPV vaccine trial here. Notice that the paper was published in 2000 and it took roughly another decade before the vaccine was distributed.

"Before the question of drug or vaccine efficacy can be answered, safety testing, validation of mechanism, and specificity issues must be addressed in preliminary studies. These studies themselves often provide unexpected information that generates new hypotheses. An efficacy trial, usually a randomized controlled trial‚ represents the ultimate test of concept that an intervention can ameliorate disease or prevent infection [2]."

Phase I and II trials are also important for hypothesis raising, not just hypothesis testing. Back to the HIV example, we still don't know why it takes so long for the human body to produce antibodies able to recognize a broad spectrum of HIV strains. We still don't know why a small percent of HIV-infected subjects, the so called "elite-controllers", are able to keep their viral load down to undetectable for decades. We still don't have biomarkers that predict the strength of an immunological response to the vaccine. People who make strong antibodies, they make them later in the infections, when it's too late to clear the virus. Elite controllers, on the other hand, have very low antibody titers.

Finally, to make things even more complicated, the animal models used to test vaccines are not good predictors of the human immune system. For examples, vaccinated macaques have been challenged with SIV, the simian immunodeficiency virus, which is a much older virus than HIV. There are ways to "humanize" the monkeys, but they can never 100% predict the human trial. And that's why we've been eagerly waiting for phase I of the mosaic vaccine... unfortunately, we are still waiting. I should have an update soon, though, as I'm heading out to see our collaborators later this week. Stay tuned!

[1] Supachai Rerks-Ngarm, et al. (2009). Vaccination with ALVAC and AIDSVAX to Prevent HIV-1 Infection in Thailand N Engl J Med DOI: 10.1783/147118910790291082

[2] Lawrence Corey, Gary J. Nabel, Carl Dieffenbach, Peter Gilbert, Barton F. Haynes, Margaret Johnston, James Kublin, H. Clifford Lane, Giuseppe Pantaleo, Louis J. Picker and Anthony S. Fauci (2011). HIV-1 Vaccines and Adaptive Trial Designs Sci Transl Med DOI: 10.1126/scitranslmed.3001863

The Departure

Just uploaded to my portfolio. Texture this time courtesy of the incredibly talented fine art photographer Brooke Shaden. Thanks for being such a great inspiration, Brooke!

Bacteria to the rescue!

Last month I talked about a cancer killing virus. Well, guess what comes next? A cancer killing bacterium, of course! :-) Our hero is once again, the one and only E. coli, a bacteria that normally resides in our guts and that is much beloved by experimentalists because it's cheap and easy to grow.

In 2011, a group from Nanyang Technological University, in Singapore, genetically modified a strain of E. coli so it would sense and kill the human pathogen Pseudomonas aeruginosa[1], a bacterium responsible for infections that can be lethal in immunochallenged subjects. Pseudomonas aeruginosa is resistant to many currently available antibiotics. On the other hand, therapies that do succeed in killing the bacterium also kill other bacteria that are part of a healthy microbiome.

How to eradicate a Pseudomonas aeruginosa infection without harming the "good" bacteria, then?

When in highly competitive environments, bacteria produce toxins, called bacteriocins, that kill closely related, competing strains. The bacteriocin that Pseudomonas aeruginosa produces is a toxic peptide called pyocin. The advantage of using such toxins instead of antibiotics is that, while resistance to antibiotics appears relatively early after therapy thanks to lateral transfer, no toxin-resistant strains have been observed so far.

"Given the stalled development of new antibiotics and the increasing emergence of multidrug-resistant pathogens, using synthetic biology to design new treatment regimens for infectious disease could address an urgent need [1]."

So, how does the bioengineered E. coli kill the pathogens? In order to "communicate" with one another, bacteria release a number of chemicals whose concentrations are proportional to the population density. These exchanges are called "intercellular quorum communication", or quorum sensing, and enable bacteria to turn "on" or "off" gene expression depending on the surrounding cell density of the population (i.e. when the concentration of molecules signaling a certain status reach a specific threshold). One of such mechanisms regulates the production of pyocin. Saeidi et al. [1] reproduced this regulatory mechanisms to enable their bioengineered E. coli to "sense" the presence of Pseudomonas aeruginosa, release the toxin, and kill it.

"Upon reaching a threshold concentration, the lysis E7 protein perforates membrane of the E. coli host and releases the accumulated pyocin S5. Pyocin S5, which is a soluble protein, then diffuses toward the target pathogen and damages its cellular integrity, thereby killing it [1]."

But wait, what about cancer? Eradicating cancer faces similar issues: you need to kill all the "sick" cells without harming the healthy ones. Chemotherapy drugs often end up damaging healthy cells too, hence the need of "targeted" drugs, drugs that can be delivered exclusively to the cancer cells.

A group from the University of Maryland used the quorum sensing mechanisms intrinsic in the bacterium to make it sense cancer cells. And while it doesn't quite kill the cancer cells, this research is important because the bacterium could become a means to transport specific drugs to the cancer tissues, while leaving the healthy cells untouched.

"By altering their quorum sensing genetic circuits, we engineered bacteria to find cells of interest (diseased or otherwise), dock on associated surface receptors or biomarkers (‘features’), integrate surface feature density, and also decide whether or not to initiate gene expression. This ‘smart’ bacterium reinforces the notion of an expanded synthetic biology umbrella that confers new capabilities on the individual cell. The resultant cell has capabilities that could be viewed as analogous to a dirigible—a transport vehicle that autonomously navigates and carries or deploys important cargo [2]."

The principle is the following: 1. find a biomarker that can "flag" the target cell and distinguish them from the healthy cells; 2. using the biomarkers as flags, deploy "nanofactories" to the target cell and have them produce the "quorum sensing" chemicals; 3. once quorum sensing is triggered, the bioengineered E. coli "swim" to the target cells.

Nanofactories are made of an antibody motif for binding to the cell and a fusion protein that produces quorum molecules when bound to the targeted bacterium [3]. In [2], Wu et al. used squamous cancer cells of the head and neck as target cells. These express EGFR, epidermal growth factor receptor, at a high threshold, which was used as biomarker. The nanofactories bound to EGFR and synthesized AI-2, the quorum sensing molecule that stimulated E. coli motility.

"In summary, the docking of anti-EGFR-NF onto mammalian cell surfaces was specifically controlled by EGFR surface density which, in turn, controlled subsequent AI-2 synthesis, bacteria migration, and the switching response phenotype. The signal generating and cell recruiting design shown here provides a tractable means to ensure site-specific gene initiation, providing a focused and predicted phenotype."

In the future, the cancer-sensing E. coli could become an efficient transporter of drugs aimed at destroying cancer cells while leaving the healthy cells intact.

[1] Nazanin Saeidi, Choon Kit Wong, Tat-Ming Lo, Hung Xuan Nguyen, Hua Ling, Susanna Su Jan Leong, Chueh Loo Poh & Matthew Wook Chang (2011). Engineering microbes to sense and eradicate Pseudomonas aeruginosa, a human pathogen Molecular Systems Biology DOI: 10.1038/msb.2011.55

[2] Hsuan-Chen Wu, Chen-Yu Tsao, David N Quan, Yi Cheng, Matthew D Servinsky, Karen K Carter, Kathleen J Jee, Jessica L Terrell, Amin Zargar, Gary W Rubloff, Gregory F Payne, James J Valdes & William E Bentley (2013). Autonomous bacterial localization and gene expression based on nearby cell receptor density Molecular Systems Biology DOI: 10.1038/msb.2012.71

[3] Rohan Fernandes, Varnika Roy, Hsuan-Chen Wu & William E. Bentley (2010). Engineered biological nanofactories trigger quorum sensing response in targeted bacteria nature nanotechnology DOI: 10.1038/nnano.2009.457

Save the date!

My first "solo" show is in two weeks! I will be at the Silver Sun Gallery at 656, Canyon Road, in Santa Fe, NM, for the opening reception on Friday September 27 from 5 p.m. to 7 p.m.

Hope to see you there!

For a preview of what you'll see at the show, please visit my portfolio.

Afterthoughts

As always, prints are available here.

The HPV vaccine: a few things you should know

If you are a young woman under 25 years of age, or if you have a teenager at home, chances are, your doctor told you about the HPV vaccine. HPV, or Human Papillomavirus is a DNA virus that infects keratinocytes, cells found in the epidermis and in mucous membranes. Though in some cases the virus causes painful warts, HPV infections are often asymptomatic. So why bother screening an asymptomatic virus? Because while the majority of the infected people clear the virus within 1-2 years, in less than 10% of the cases the infection persists and can, eventually, lead to cancer.

Studies have shown that cancer is linked to persistent infections, and that on average it takes around 5 years to reach a pre-cancer state [1]:

"Persistent infections and precancer are established, typically within 5-10 years, from less than 10% of new infections. Invasive cancer arises over many years, even decades, in a minority of women with precancer, with a peak or plateau in risk at about 35-55 years of age [1]."

Unfortunately, there are no screenings currently available for HPV in men or infections that do not pertain the cervix. For cervical cancer in women, the current recommendation is to get a pap smear every 2-3 years, which has been highly effective in reducing the incidence of HPV-caused cervical cancers.

Like HIV, HPV has a highly diverse subpopulation: there are over one hundred different types of HPV strains, of which, only a small subset (less than 20) are carcinogenic. According to the CDC, about 26,000 cancers every year in the United States are caused by HPV, which is why the CDC recommends teenagers to be vaccinated, girls in particular:

"There are two [FDA-approved] HPV vaccines available (Gardasil and Cervarix) which protect against the types of HPV infection that cause most cervical cancers (HPV types 16 and 18). Both vaccines should be given as a three-shot series. Clinical trials and post-licensure monitoring data show that both vaccines are safe."

Types 16 and 18 are associated with slower viral clearance [1] and have been linked to about 70% of cervical cancers and 85% of anal cancers [2]. Because the vaccines are most effective prior to any exposure to the virus, the current recommendation is to administer the shots within the 13-25 age bracket.

So then the vaccine seems a good idea, right?

I certainly thought so until my friend Alex brought up the news that last June Japan withdrew HPV vaccine reccomendations.

"According to a report in the Japan Times, 8.29 million people had received the HPV vaccine as of December 2012, and there were 1968 cases of concerning adverse events reported as of March 2013. Of these adverse events, 106 were described as "serious cases of pains or body convulsions, pains in joints, or difficulty in walking."

And while all vaccines bring some risks, but the risks are outnumbered by the lives they save, if you do the math you'll find that

"Those numbers translate to a rate of 12.8 serious cases of adverse events per 1 million inoculations, according to the report. This compares unfavorably with the 0.9 serious adverse events per million influenza inoculations in Japan and the 2.1 serious adverse events per million inoculations of inactivated polio vaccine."

So I went back to the CDC page, found that nothing had changed in their recommendations, however, I found a transcript of a CDC press briefing from June 2012, in which a CDC employee claimed that they had found about a dozen US reports similar to the adverse cases reported in Japan, but that no causality had been established.

In the literature, I found a report that advocates for reforms in the Japanese vaccination program:

"This directive [to stop recommending the HPV vaccine] was issued due to fears of adverse events, especially complex regional pain syndrome. However, the present system of reporting adverse events does not follow a systematic process for identifying causality; a rigorous scientific approach is needed to investigate adverse events associated with HPV vaccines. [...] Japan's vaccination system suffers from a failure of governance—also reflected in other aspects of the vaccination schedule. Mumps, adult pneumococcal, rotavirus, and hepatitis B vaccines have yet to be introduced in the routine schedule, even though they are recommended by WHO."

What's the take home message out of all this?

You know I work on HIV vaccine design and I'm a long-time advocate for vaccines. If you look back in time, vaccines have saved far more lives than the supposed adverse effects. Our immune system is a brilliant machinery designed to recognize self from non-self and destroy whatever falls in the latter category. It's built on both genetics (native immunity) and experience (acquired immunity), as it constantly retunes to allow the body to adapt to a changing environment. Messing up with the immune system can have unforeseen, permanent consequences.

It takes decades for a vaccine to go from design to marketing. It needs to be tested on animals before it is tested on humans. The first phase I trials on humans have the sole "safety" objective, in other words, even before we know whether the vaccine is effective in preventive a certain disease, we need to prove it is safe to use and causes non harm. Neither vaccine would have been FDA approved had they not passed all the safety requirements.

This means that if you search the literature, you will find published studies on the safety of for either the Gardasil or the Cervarix HPV vaccines. For example, I found a pooled analysis of 11 cohorts published by Landes Bioscience, in which you can find all statistics of adverse effects, from a common headache to more serious ones. In their discussion, the authors (affiliated with GlaxoSmithKline Biologicals) bring up the fact that there could be a correlation between underlying auto-immune disorders and the reported adverse effects, and that a direct causality with the HPV vaccine, once again, could not be established.

At the end of the day, we are individuals, not statistics. It's fine to read that a certain condition or side effect is so rare it happens once in a billion cases, yet we don't want to be that one in a billion case. HPV is more likely to cause cancer in smokers. Maintaining a healthy life should be our foremost priority. For cervical cancer in particular (which covers the vast majority of HPV-caused cancers), given how long it takes for the virus to establish a persistent infection, doing the pap test every other year will likely catch the infection before it gets to a precancer stage.

Do your homework. Read. Exercise. Eat healthy. Then do more homework. It's your life, make informed decisions.

[1] Helen Trottier, Salaheddin Mahmud, José Carlos M Prado3, Joao S Sobrinho, Maria C Costa, Thomas E Rohan, Luisa L Villa and Eduardo L Franco (2008). Type-Specific Duration of Human Papillomavirus Infection: Implications for Human Papillomavirus Screening and Vaccination Infectious Diseases DOI: 10.1086/587698

[2] Schiffman M, Castle PE, Jeronimo J, Rodriguez AC, & Wacholder S (2007). Human papillomavirus and cervical cancer. Lancet, 370 (9590), 890-907 PMID: 17826171

Doors

Two Doors by EEG

This image popped into my head last night.
Many thanks to Joel Olives for sharing his awesome textures.

Happy Friday!

Images, images, images

The show is in 4 weeks. A little less, actually.

Am I nervous?
Yes.

Am I excited?
YES!

I just ordered canvas prints for the last two images and then I'm all set to go. Let me tell you a bit about both, because, as you can tell, they are very different.

Macondo Dreams by EEG

For this image I had the model first, which almost never happens. She's a beautiful young lady visiting from Italy and as soon as I met her I thought of one of my favorite painters, Dante Gabriel Rossetti. Luckily, she didn't object when I asked her to pose for me. The title came after my mom, looking at this image, reminded me of my favorite book of all times: One Hundred Years of Solitude. Lots of favorites in this image. :-)

Down the Rabbit Hole by EEG

For this second image I had the idea first, which is not always a good thing as I often end up with something totally different than what I originally had in mind. I wanted to show a woman falling down the Rabbit's Hole. I wanted a very dramatic pose and a very dramatic dress. Adding drama over drama, she ended up looking dead. While by all means not the picture you'd want to hang in your living room, I think this is an attention grabber, so it'll go in the show. If nothing else, I'm hoping it'll draw some curiosity in a casual passer-by, enough to make them want to step inside the gallery. :-)