New approaches are needed to reverse the trend of disappointing vaccines against HIV/AIDS, tuberculosis and malaria, argues biotech expert Thomas Egwang.
Developing countries have waited and waited for malaria, HIV/AIDS and tuberculosis (TB) vaccines. Unfortunately, those tested so far, such as RTS,S/AS01 and MVA85A are long on safety but short on efficacy.
This is because the empirical 'clone and test' method of vaccine development has relegated studies of protective immunity and the mode of vaccine action to the back burner.
HIV/AIDS vaccines have had a checkered history since the first clinical trials in 1987, with some trials halted due to safety concerns; outright failure in phase III trials; and then a single flash of success when RV144 protected 31 per cent of 16,000 Thai volunteers. 
- Current efforts are failing to deliver effective vaccines
- Shortcomings include single-antigen strategy and poor knowledge of immunity
- Future efforts should revisit old approaches such as whole-organism vaccines
BCG (Bacille Calmette-Guérin), which was developed in 1921 but is still the only licensed vaccine against TB, is used to vaccinate 100 million newborn infants a year. It has limited efficacy in children and does not protect adults from the pulmonary form of the disease.
A new vaccine, MVA85A, was designed as a booster for BCG. But in a recent phase IIb trial, this promising candidate to boost BCG provided only 17 per cent protection for babies. 
The leading malaria vaccine candidate, RTS,S/AS01, protected only a third of six- to 12-week-old infants.  But proponents maintain that this level of protection could mean 200,000 fewer infants dying of malaria each year.
Interestingly, in other trials, RTS,S/AS01 provided a substantially higher protection in older infants and in infants of the same age.
All these vaccines were developed by cloning and expressing one or several pathogen antigens — immunity-inducing substances — in various vectors.
The cloning of one type of protein (circumsporozite) from the malaria parasite Plasmodium falciparum in 1983 was a watershed. Parasite proteins could now be produced in unlimited quantities for vaccine research. This spawned the hope that a malaria vaccine was just around the corner.
Three decades later, the wait continues.
Vaccine development strategies related to HIV and the TB bacteria, Mycobacterium tuberculosis, have followed a similar path: antigens were cloned and stitched into vectors, and administered to animals for proof of concept.
Laudable as these efforts have been in producing vaccines with acceptable safety and tolerability, they failed to deliver on efficacy because of two shortcomings.
First, the mechanisms by which vaccine candidates induce protective immunity in the few animals or individuals they protect have not been thoroughly investigated. This has resulted in a lack of reliable and robust correlates or biomarkers that indicate vaccine-induced protective immunity.
Validated biomarkers or correlates can guide vaccine development from the outset, winnowing out duds before they reach expensive clinical trials. Otherwise, clinical trials become hugely expensive exercises in trial and error.
The second shortcoming is that current vaccines consist of single antigens. Yet during natural malaria infection, more than 5,300 P. falciparum proteins are presented to the immune system and, even then, only partial protective immunity develops after several years.
To expect a whopping vaccine efficacy with single antigen vaccines is a pipe dream.
Targeted studies needed
The way forward must start by mining clinical materials and information from the RV144, RTS,S/AS01, MVA85A and other trials for valuable insights about vaccine-induced protective immunity.
The RTS,S/AS01 and MVA85A vaccines targeted young infants. But important insights about immune responses in infants were not considered.
For example, we know that the infant immune system is immature; infants acquire critical maternal immunological factors via their mother's placenta or by breast-feeding; maternal antibodies and infant age at the time of vaccine administration affect vaccine responses; and malaria endemicity and infant age influence immunity against malaria.
The design of future infant vaccines and clinical trials should be informed by this knowledge and other new insights.
Similarly, in the case of HIV, studies focusing on peripheral blood mononuclear cells that are never on the front line in the defence against sexually transmitted infections are unimaginative. Innovative strategies that stimulate potent protection against HIV in the genitourinary tract are long overdue.
Correlates or markers of protective immunity must be identified in the lung for TB; the skin, liver and blood for malaria; and the genitourinary tract and rectum for HIV.
This must be complemented with a concerted move towards multi-antigen vaccines that stimulate protective immune responses comparable with those induced by natural infection. However, the best permutations and combinations of antigens still have to be empirically determined by costly clinical trial and error.
Whole-organism vaccines, after years of neglect, offer promise. They embody the multi-antigen concept and have proven themselves in whooping cough (pertussis), typhoid, flu and polio vaccines.
A promising genetically modified killed whole HIV-1 vaccine (SAV001-H) is poised to enter further clinical trials. So are irradiated whole malaria sporozoite vaccines (PfSPZ), which confer more than 90 per cent protection in human volunteers. 
A self-replicating synthetic bacterial TB vaccine with high protective efficacy — and no pathogenicity — would herald TB eradication. The technology platform and precedence for such a feat exists.
Whichever path is taken, malaria, HIV/AIDS and TB vaccinology must refocus on rational rather than empirical immunological investigations and embrace bold and innovative strategies. An old approach with a new twist might shorten the long wait for vital vaccines.
Thomas Egwang is director general of Med Biotech Laboratories in Uganda. He was principal investigator for a malaria vaccine phase I trial in northern Uganda in 2010/2011. Egwang can be contacted at firstname.lastname@example.org
 AIDS Research and Human Retroviruses doi: 10.1089/aid.2012.0103 (2012)
 The Lancet doi:10.1016/S0140-6736(13)60177-4 (2013)
 The New England Journal of Medicine doi: 10.1056/NEJMoa1208394 (2012)
 Hoffman, S.L. et al Development of a metabolically active, non-replicating sporozoite vaccine to prevent Plasmodium falciparum malaria (Human Vaccines, January 2010)