Sang Froid in a time of trouble: is a vaccine against HIV possible?

Abstract

Since the announcement of the STEP trial results in the past months, we have heard many sober pronouncements on the possibility of an HIV vaccine. On the other hand, optimistic quotations have been liberally used, from Shakespeare's Henry V's "Once more unto the breach, dear friends" to Winston Churchill's definition of success as "going from one failure to another with no loss of enthusiasm". I will forgo optimistic quotations for the phrase "Sang Froid", which translates literally from the French as "cold blood"; what it really means is to avoid panic when things look bad, to step back and coolly evaluate the situation. This is not to counsel easy optimism or to fly in face of the facts, but I believe that while the situation is serious, it is not desperate.I should stipulate at the outset that I am neither an immunologist nor an expert in HIV, but someone who has spent his life in vaccine development. What I will try to do is to provide a point of view from that experience.There is no doubt that the results of STEP were disappointing: not only did the vaccine fail to control viral load, but may have adversely affected susceptibility to infection. But HIV is not the only vaccine to experience difficulties; what lessons can we glean from prior vaccine development?

Figure 1

Neutralizing antibodies in patients with resolved or chronic hepatitis C.

Figure 2

Control of High SHIV Viral Load by CD8+ Cells After Vaccination.

Figure 3

Control of High SIV Viral Load by cellular Responses to DNA/Adeno Vaccination.

Figure 4

Acquisition of HIV by Kenyan Sex Workers Prevented by Genital IgA and Systemic T Cell Proliferation. Obviously, there are many problems to solve in attempting mucosal immunization. One approach is to mix routes of administration, for example priming with oral vaccination and following with parenteral boost. Moreover, it is not impossible to consider mixed intranasal and intrarectal administration to immunize both the genital and gastrointestinal tract. Aerosol administration of HPV vaccine has been reported to induce IgA secreting cells in the genital tract [115], and there is recent work suggesting that sublingual administration of antigens may be a way around compartmentalization of mucosal immunity [116] (see table 7).