Vaccine Guru

A promising new study shows that a recombinant chimp adenovirus-3 vaccine vector carrying the surface glycoproteins of Zaire and Sudan strains of Ebola virus was safe and immunogenic in 20 volunteers. There were 11 women and 9 men in the study and the ages ranged from 25-50. Results 1. What looked really promising was that in about 70-90% of the participants, the vaccine induced antibodies to  Zaire and Sudan glycoproteins. 2. Glycoprotein-specific memory CD4 and CD8 T cell responses were polyfunctional and the vaccine elicited high proportions of CD8 cells co-producing interferon-g and TNF. 3. Pre-existing antibodies against adenovirus-3 did not significantly correlated with the magnitude of vaccine-induced memory CD4 T cell response. Remarks * While the CD4 T cell shows no significant change in cytokine response with increased particle units, the polyfunctionality of CD8 T cells shows a significant change. * The graphs representing "Total Cytokine Response shown a

In a recent study from the Zoster-015 HZ/su study group headed by GSK,  a Phase I/II randomized, placebo controlled study to evaluate the safety and immunogenicity of an investigational herpes zoster subunit vaccine was performed. To briefly provide a background to the study, the incidence of shingles in HIV-infected adults is 10-20 times higher than in an age-matched general population. This reduced upon the introduction of anti-retroviral therapy but remains 3-5 times higher than in the general population. Vaccination offers protection against shingles and its complications in HIV-infected patients but the use of the vaccine in immunocompromised individuals is fraught with risk due to the potential to cause disease. This necessitated a need to develop a subunit vaccine against shingles. Method: Vaccine: The subunit vaccine consisted of the VZv gE antigen along with an adjuvant. The vaccine was  administered to HIV+ patients who were ART/high CD4, ART/low CD4 and ART naive/high

Google Doodle celebrates Dr Salk, who developed one of the best and most effective vaccines ever.

A recent article found on finalcall.com is making the rounds on social media.  In a nutshell, the Minister of the Nation of Islam claims that the western world conducted a massive clinical trial of an Ebola vaccine just before the latest  outbreak in West Africa that killed several thousands. Again conspiracy theorists are out to make Ebola as a man-made disaster that is killing Africans. There are some true facts in the story, particularly those about ZMapp being made available to a select few and not available to a large number of patients, especially poor Africans! It would have created quite an outrage if the ZMapp antibody was administered to poor Africans and many died!! The fact that it was tried on some Americans point to the fact that ZMapp did not want to be named and shamed as a company that uses poor Africans as guinea pigs. It is pathetic that scientific facts are not debated intelligently before publication in obscure publications that promote conspiracy theories.

Nobel Laureate David Baltimore presented his findings  at the Lou Siminovitch Lecture in Toronto and gave a glimpse of all the recent findings related to the plethora of antibodies that are known to bind to HIV. Many of these have broad specificities and high affinities. It is a fun time for antibody research considering the advances made in deciphering the crystal structure of the viral glycoprotein. Baltimore introduced the work of his lab, particularly that of Alex Balazs, in developing a novel form of therapeutics. Termed "Vectored ImmunoProphylaxis" or VIP, the concept is that of getting the body to make antibodies against the virus. Basically, Baltimore and Balazs engineered an Adeno-associated Virus (AAV) which has a small genome to express the heavy and light chains of their favourite antibody. This could be against HIV, Hepatitis or Malaria. The virus is injected into the muscle of mice where the vector starts expressing the antibody protein. When the mouse is

A recent paper by Li et al., from the lab of Dan Barouch at Harvard shows very interesting results based on observations made from Rhesus macaques injected with experimental HIV vaccines.  One of the key questions facing HIV vaccine researchers is whether one should design vaccine that stands a fair chance at inducing an immune response in the genital mucosa, since this is the portal of entry for the virus. The mucosal immune response is a key factor in vaccine efficacy and success against infection or disease progression. This paper that appeared in Journal of Virology (doi: 10.1128/JVI.02095-14) first determined that the amount of IgG in serum was significantly higher than IgA whereas the amount of IgA in colorectal mucosal secretions was significantly higher than IgG. They also confirmed that IgA from mucosal secretions was largely secretory IgA and not serum contamination. Next, they injected rhesus macaques with candidate HIV vaccines. 16 animals were injected (i.m.) with Ad

PedVacc 002: Njuguna et al., Vaccine (2014). After a clinical trial evaluating safety of a modified vaccinia virus Ankara (MVA) expressing HIV in infants born to HIV-1 negative mothers in Gambia (PedVacc001 trial), a research group working out of Nairobi tested the vaccine in another clinical trial (PedVacc002) in Kenya to test the safety of the vaccine, which was the primary outcome. The latter trial however was carried out in infants born to HIV-1-positive mothers. The vaccine was well tolerated with very rare adverse events that were similar between vaccine and no-treatment arms. The MVA-HIVA was safe but no sufficiently immunogenic in infants. The immune response of the infants to all routine childhood vaccines was also tested and interestingly, while 92% of the control subjects were found to have protective antibodies against Hepatitis B virus, only 71% of the vaccinees showed a similar effect and this was statistically significant (p=0.05). This difference was not observed

While the world is trying to recover from the scandal that plagued the vaccine field due to the infamous link to autism (read Andrew Wakefield's story), the issue is still in the minds of moms and dads everywhere. While hopefully, the link between MMR vaccines and autism stays debunked at least in the scientific world where data alone triumphs, there have been issues with vaccines and will continue to do so. Nothing is ever perfect. Between June 2006 and March 2014, approximately 67 million doses of HPV vaccines were distributed and the Vaccine Adverse Event Reporting System (VAERS) received approximately 25,000 adverse event reports occurring in girls and women who received HPV vaccines and of these, 92% were classified as 'non-serious', suggesting 2000 cases were serious. Should we be rethinking vaccine formulations? In another controversial decision, the journal Translational Neurodegeneration  (paper by Brian Hooker) removed a paper that was published, citing serio

Apparently, there is not enough experimental therapeutic drug (ZMapp) to go around treating everyone infected by Ebola virus. Of 6 patients who have been treated, 2 have recovered and headed home. The 6 are Dr Brantly, Ms Writebol, Fr. Miguel Pajares (deceased), Dr Zukunis Ireland, Dr Abraham Borbor (deceased) and Dr Aroh Cosmos Izchukwu. While the fate of the other survivors are not known yet, the amazing recovery of Dr Brantly ( Just came to know through Samaritan's Purse that Dr Brantly had previous to ZMapp treatment, also  received serum from a 14 year old survivor of Ebola)  and Ms Writebol, pushed global interest in these therapeutic drugs. It also raised the profile of Canadian scientists (Dr Gary Kobinger) who are involved in developing this treatment.  The drug that is being used here is a cocktail of 3 antibodies to Zaire Ebola virus surface glycoproteins. These humanized monoclonal antibodies combine the best components of MB-003 aka Mapp [1 mAb from MB-003] and ZMa

http://mosaicscience.com/story/francoise-barre-sinoussi An interesting article that is full of life, yet poignant, considering the lives lost to the disease and the impact of a discovery on the strained relationships between scientists. A terrific article describing the life and work of Francoise Barre-Sinoussi, the co-discoverer of the HIV virus.

A recent paper by a multi-center group looking into the famous "31.2% vaccine efficacy" study (RV144 trial) shows interesting features associated with this protection against HIV-1. Shuying Li looked at vaccine-induced Fc receptor-mediated antibody function and in this paper, show that a single nucleotide polymorphism in the FcR-encoding genes is strongly associated with protection. Individuals with a  SNP (rs114945036) carrying CC in this SNP had a vaccine efficacy of 15% while those with a CT or TT had a vaccine efficacy of 91% against HIV-1 subtype CRF01_AE with a lysine at position 169 (169K) in the V2 loop. RV144 is a treasure trove of discoveries. The world is eagerly waiting for more data and a cure! This has been tweeted: Joe L Sosa Jr  ‏ @ TweetSosa     21m In Study of HIV Vaccine Trial Subjects, Genotype Defines Subsets with Strong and Weak Response http:// dlvr.it/6gQWts

The virus that was discovered in the late 70s in the Belgian Congo has now struck fear and panic in West Africa. The therapy that is widely believed to cure the patient infected with Ebola virus is plantibody: Essentially, the gene encoding the antibody is genetically expressed as a protein in the humble tobacco plant. Several companies are working on producing recombinant proteins in Plants-PlantForm in Canada and the now famous Zapp biotech company in the US. Ebola is a scary pathogen because mortality is rapid and almost certain. Ebola, curiously, also uses Tim-3 on cells to enter and cause pathogenicity. Interestingly, Tim-3 is highly expressed in T cells that are exhausted in HIV-1 disease. Does this mean that HIV-1 patients who express higher levels of Tim-3 have a higher chance of getting infected with Ebola. Now that is scary indeed! Whether the cell types that express Tim-3 are infected by HIV-1 needs to be investigated!

In a fantastic new paper by Chung et al., (2014) that accompanied the paper described in my previous Blog by Yates et al., (2014), the role played by IgG3 has been described very elegantly in the context of 2 HIV vaccines-RV144 and VAX003. Chung et al., show how IgG3 might be able to fight HIV infection in the absence of viral neutralization. Background: RV144: ALVAC-HIVvCP1521 prime and recombinant gp120 AIDSVAX B/E boose                      VAX003: AIDSVAX B/E bivalent rgp120 given with alum in 7 doses Results: * RV144 elicited a polyfunctional antibody response associated with the selective induction of IgG3 antibodies. * VAX003 elicited a monofunctional antibody response characterized by selection of the functionally inert IgG4 antibody subclass, likely due to repeated administration of gp120 protein vaccination which decreased IgG3 subclass levels. *RV144 induced both IgG1 and IgG3 antibodies targeting the V2 crown, whereas VAX003 induced an IgG4 antibody response agai

There have been a series of papers describing the " Antibody Profile " of participants in the partially successful RV144 Trial that I had described earlier. The first paper looking at the antibody type is a paper by Nicole Yates that appeared in Science Trans Med (2014) . Very little is known about the protective role of vaccine-induced IgG3 antibodies for HIV-1. Previously, it was found that a best known anti-HIV-1 antibody, 2F5, is of IgG3 origin. In the paper by Yates et al., they compared antibody profiles of RV144 trial and the VAX003 trial, which was a modification of the RV144 vaccine. Background: RV144 consists of (cladeB/E) ALVAC prime plus 2 protein boosts rgp120 boost VAX003: consists of (cladeB/E) gp120 protein immunogen. Results: *It was found that IgG3 response rates were significantly higher in RV144 compared to VAX003 at peak immunogenicity time point. **V1-V2 IgG3 antibodies correlated with decreased risk of infection in RV144.

 From T cells to Antibodies: Back and Forth search for an ideal HIV vaccine With negative data pouring out of major Clinical Trials associated with  HIV-1 vaccines, even though some are encouraging, emphasis has shifted from T cell-based vaccines to Antibody-based vaccines. This is mainly due to precise determination of HIV-1 protein structure, that has been corroborated by several laboratories. Additionally, the isolation of broadly neutralizing antibodies from patients who resist the disease (CAPRISA), further invigorated the vaccine community. What does this mean for vector development? Louis Picker's groundbreaking study in Rhesus macaques showing significant protection against SIV challenge using a cytomegalovirus vector determined that the mechanism is due to an unconventional induction of CD8 T cell response restricted by MHC class II proteins. Is this system unique to SIV? Will this work in HIV? While it is too early to tell, the next best experiment would be to condu

  A Phase III Trial of Sanofi Pasteur Live Recombinant ALVAC-HIV (vCP1521) Priming With VaxGen gp120 B/E (AIDSVAX B/E) Boosting in HIV-Uninfected Thai Adults. Background: RV114 was a Prevention, Randomized, Double Blind (Subject, Caregiver, Investigator), Placebo Control, Parallel Assignment, Efficacy Study carried out in Thailand. This prime-boost test-of-concept trial began in 2003 and enrolled 15403 HIV-negative Thai men and women between the ages of 18 and 30. The vaccine consisted of 2 regimens: ALVAC (prime) and AIDSVAX B/E (boost). The vaccine consisted of synthetic fragments of genetic components of HIV- subtypes B and E (CRF01 AE).  End points: Whether vaccine reduced risk of HIV infection and whether vaccinated individuals who acquired HIV had lower viral loads than placebo group. To determine statistical significance, data were analyzed according to 1. Intent to treat (ITT) 2. Modified Intent to treat (mITT) and 3. Per Protocol (PP). Results:

HVTN/STEP Trial: A vaccine that surprised many with increased risk of disease in vaccinees: A Phase IIb ‘test of concept’ trial of Merck’s MRKAd5 HIV-1 gag/pol/nef trivalent vaccine based on a weakened non-replicating adenovirus (type 5 adenovirus). This was a Randomized, double blind, placebo control study carried out in North America, South America, Caribbean and Australia This trial enrolled 3000 adult HIV negative high-risk population from a diverse background (gay/MSM, female sex workers 18-45 years of age). The study had 62% males and 38% females. First enrolment was in Dec 2004 and the enrolment was completed in March 2007. The primary efficacy endpoints: Whether the vaccine prevented HIV infection and whether the vaccine reduced the viral load in those who were infected. Results: The vaccine did not prevent infection: in the 741 volunteers who received at least one dose of the three-dose vaccine series, 24 cases of HIV infection were observed and 21 cases of HIV