This past Wednesday, September 28, the Spanish Superior Scientific Research Council (CSIC, Consejo Superior de Investigaciones Científicas) issued a press release about the results of a phase I HIV vaccine trial involving 30 uninfected volunteers. The release refers to two recently published papers, one made available online by the journal Vaccine on September 9, the other by J. Virology on August 24 (abstracts and links below). The trial used a very common vector, modified vaccinia Ankara strain (MVA, a highly attenuated member of the poxvirus family), to deliver HIV antigens, and studied the resulting immune responses (24 participants received vaccine, 6 placebo). The results were a little better than those obtained with some other MVA vectors, but similar to responses seen with adenovirus-based vectors like the Ad5 HIV vaccine developed by Merck, which failed to show any efficacy at either preventing or controlling HIV infection in a widely-publicized phase IIb trial (the STEP study).
So far, so average. But the press release went a little overboard in attempting to sell the results to the media, triggering some of the most woefully misleading and erroneous coverage of HIV vaccine research in recent memory. Here are just a few examples of the headlines:
In isolation, the missteps in the press release are not particularly or uniquely heinous: the headline is "MVA-B Spanish HIV vaccine shows 90 percent immune response in humans." This refers to cherry-picked data derived from an analysis of either CD4 or CD8 responses to HIV antigens in a subset of 13 vaccine recipients described in the J. Virology paper; these individuals were selected because they attended a trial site in Madrid that could quickly deliver the fresh blood samples needed for the particular assay used (intracellular cytokine staining). Similarly, the press release trumpets an 85% response rate at week 48 of the study that is also derived from this 13-person subset. The Vaccine paper reports an analysis of CD4 or CD8 T cell responses in the full cohort of vaccine recipients (minus two individuals lost to follow up) at week 48 using an ELISPOT assay; the result is less impressive-sounding at 68% (15/22). The press release should have been upfront about this of course, but it’s not unusual for researchers to try and put their best-sounding data forward.
Two other missteps in the release make key contributions to the maelstrom of misinformation. The first is that the senior author of the papers, Mariano Esteban, is quoted as saying:
"MVA-B vaccine has proven to be as powerful as any other vaccine currently being studied, or even more"
In the original Spanish release, "powerful" is "potente," and I think it’s reasonable to assume that what Esteban was trying to convey is that the vaccine is as immunogenic as any other candidate out there, which isn’t an unreasonable claim. But since immunogenic is an obscure technical term for the ability of a vaccine to induce immune responses (without regard to whether there is any evidence that those immune responses are effective), a more understandable word was substituted—unfortunately one that could easily be misinterpreted as implying powerful efficacy.
Lastly, the release concludes:
"According to CSIC's researcher: 'If this genetic cocktail passes Phase II and Phase III future clinic trials, and makes it into production, in the future HIV could be compared to herpes virus nowadays'. Virus would not cause a disease anymore and would become a minor chronic infection, which would only show its effects in a low defence scenario, with a much lower contagious profile."
This is perhaps an attempt to paint an optimistic picture of what a vaccine that controlled but did not prevent HIV infection might achieve, and it does include an "if," but it is nevertheless so ripe for misinterpretation as to be foolhardy at best, and irresponsible at worst. Combined with the other potentially misleading elements of the press release, it created a perfect storm of hyperbole. Even an attempt to explain how memory T cells work became grist for misinformed articles, because many journalists are unfamiliar with the subject and thus thought that what was being described was something unique to the MVA-B vaccine (rather than just a description of memory immune responses similar to those that failed to work effectively against HIV in the STEP trial).
What makes this incident particularly dispiriting is that there is abundant background information on MVA vectors and HIV-specific immune responses available on the internet and easily accessible to any journalist who might—perish the thought—have been inclined to evaluate the CSIC release with a critical eye. Even on the simplest level, anyone writing about science should know that a 30-person phase I HIV vaccine trial can say nothing about potential efficacy.
When it comes to what the MVA-B papers actually show, they provide some evidence that the way that the CSIC researchers inserted HIV antigens into the vector may have served to increase the CD8 T cell response rate compared to other MVAs, although the CD4 T cell responses are poorer. There is no assessment of whether the CD8 T cell responses induced by MVA-B can actually kill HIV-infected cells, a parameter that has emerged as critically important for T cell-based vaccines (as Professor Esteban points out in his comment below, CD8 T cells from HIV-positive individuals primed in a lab dish by dendritic cells infected by MVA-B have been shown to kill HIV-infected CD4 cells, but it is not yet known if the same holds true for CD8 T cell responses induced by the vaccine in people). In the paper in Vaccine, the authors themselves note that immune responses are very similar to those induced by Merck’s failed Ad5-based candidate, both in terms of response rate and magnitude. Binding antibody responses are not notably different from other vaccines, and a single assay that is used to look for neutralizing antibodies only measures activity against a relatively easy-to-neutralize ("tier 1") HIV isolate named BX08; the same isolate is also the source of the HIV Env antigen used in the vaccine. Even under these artificially ideal circumstances, neutralizing antibody activity is only detected in a third of vaccine recipients.
Ultimately, in stark contrast to the wildly exaggerated claims now circulating globally, the results indicate that MVA-B will join a large group of similar poxvirus vectors that are queuing up to be considered for preventive efficacy studies. The most optimistic view is that these candidates might be able to improve on the 31% protective efficacy reported in the RV144 vaccine trial in Thailand, but there is no indication or expectation that they will render HIV as easily controlled as herpes. Therapeutic results obtained with similar vaccines have, to date, been underwhelming. There are two ongoing trials evaluating the therapeutic potential of MVA vectors in HIV-positive people, one in the UK involving a candidate developed by Oxford University, the other in the US using a DNA/MVA prime-boost approach designed by GeoVax. Further information on the HIV vaccine pipeline can be found in TAG’s annual pipeline reports and on the AVAC website.
UPDATE 10/7/2011: Professor Mariano Esteban has kindly submitted a response regarding these criticisms of the media coverage relating to MVA-B, see the comments section below. The CSIC has also updated their press release to add some caveats, along with additional information and resources for the media; the potentially misleading reference to herpes infection has been removed. It is worth noting that the unfortunate outbreak of hype around the phase I results should not be interpreted to mean that the research has no value, as there are compelling reasons to try and iteratively improve the immunogenicity of MVA vectors and Professor Esteban's research group and CSIC have made potentially important progress on that front.
Vaccine. 2011 Sep 9. [Epub ahead of print]
Safety and immunogenicity of a modified pox vector-based HIV/AIDS vaccine candidate expressing Env, Gag, Pol and Nef proteins of HIV-1 subtype B (MVA-B) in healthy HIV-1-uninfected volunteers: A phase I clinical trial (RISVAC02).
García F, Bernaldo de Quirós JC, Gómez CE, Perdiguero B, Nájera JL, Jiménez V, García-Arriaza J, Guardo AC, Pérez I, Díaz-Brito V, Conde MS, González N, Alvarez A, Alcamí J, Jiménez JL, Pich J, Arnaiz JA, Maleno MJ, León A, Muñoz-Fernández MA, Liljeström P, Weber J, Pantaleo G, Gatell JM, Plana M, Esteban M.
Hospital Clinic-IDIBAPS, Barcelona, Spain.
BACKGROUND: To investigate the safety and immunogenicity of a modified vaccinia virus Ankara vector expressing HIV-1 antigens from clade B (MVA-B), a phase-I, doubled-blind placebo-controlled trial was performed.
METHODS: 30 HIV-uninfected volunteers at low risk of HIV-1 infection were randomly allocated to receive 3 intramuscular injections (1×10(8)pfu/dose) of MVA-B (n=24) or placebo (n=6) at weeks 0, 4 and 16. All volunteers were followed 48 weeks. Primary end-points were adverse events and immunogenicity.
RESULTS: A total of 169 adverse events were reported, 164 of grade 1-2, and 5 of grade 3 (none related to vaccination). Overall 75% of the volunteers showed positive ELISPOT responses at any time point. The magnitude (median) of the total responses induced was 288SFC/10(6)PBMC at week 18. Antibody responses against Env were observed in 95% and 72% of vaccinees at week 18 and 48, respectively. HIV-1 neutralizing antibodies were detected in 33% of volunteers.
CONCLUSIONS: MVA-B was safe, well tolerated and elicited strong and durable T-cell and antibody responses in 75% and 95% of volunteers, respectively. These data support further exploration of MVA-B as an HIV-1 vaccine candidate. Clinical Trials.gov identifier: NCT00679497.
JVI Accepts, published online ahead of print on 24 August 2011
J. Virol. doi:10.1128/JVI.05165-11
Carmen Elena Gómez, José Luis Nájera, Beatriz Perdiguero, Juan García-Arriaza, Carlos Oscar S. Sorzano, Victoria Jiménez, Rubén González-Sanz, José Luis Jiménez¶, María Angeles Muñoz-Fernández¶, Juan Carlos López Bernaldo de Quirós¶, Alberto C. Guardo#, Felipe García#, José M. Gatell#, Montserrat Plana#, and Mariano Esteban,*
Centro Nacional de Biotecnología, CSIC, Madrid. Spain
¶ Hospital Gregorio Marañón, Madrid. Spain
# Hospital Clinic-IDIBAPS, Barcelona. Spain
Attenuated poxvirus vectors expressing HIV-1 antigens are considered promising HIV/AIDS vaccine candidates. Here we described the nature of T cell immune responses induced in healthy volunteers participating in a phase I clinical trial in Spain after intramuscular administration of three doses of the recombinant MVA-B expressing monomeric gp120 and the fused Gag-Pol-Nef (GPN) polyprotein of clade B. The majority (92.3%) of the volunteers immunized had a positive specific T cell response at any time post-vaccination as detected by IFN- ICS assay. The CD4+ T cell responses were predominantly Env directed, whereas the CD8+ T cell responses were similarly distributed against Env, Gag and GPN. The proportion of responders after two doses of MVA-B was similar to that obtained after the third dose of MVA-B vaccination and the responses were sustained (84.6% at week 48). Vaccine-induced CD8+ T cells to HIV-1 antigens after one year were polyfunctional and mainly distributed within the effector memory (TEM) and terminally differentiated effector memory (TEMRA) T cell populations. Anti-vector T cell responses were mostly induced by CD8+ T cells, highly polyfunctional and of TEMRA phenotype. These findings demonstrate that the poxvirus MVA-B vaccine candidate given alone is highly immunogenic, inducing broad, polyfunctional and long-lasting CD4 and CD8 T cell responses to HIV-1 antigens, with preference for TEM. Thus, on the basis of the immune profile of MVA-B in humans, this immunogen can be considered as promising HIV/AIDS vaccine candidate.