Two for the price of one: active and passive immunity from trials of experimental vaccines
We are threatened by emerging infections such as Ebola, which erupted in 2014 in West Africa and caused more than 11,000 cases. This led to a worldwide effort, on the one hand, to develop vaccines to prevent infection, and on the other to isolate antibodies for treatment. We recently showed in a paper in Cell Reports that these two interventions can be developed together as part of a trial of an experimental Ebola vaccine. Eighty-two monoclonal antibodies were isolated from human volunteers who received an Ebola experimental vaccine, in a collaborative project between our lab at the MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine; Simon Draper at the Jenner Institute; and Daniel Lightwood at the Antibody Discovery Unit, UCB Pharma. A combination of four antibodies cured all six guinea pigs of Ebola virus infection.
Vaccines are designed to induce “active” immunity by inoculating a person with a harmless copy or component of a virulent infectious agent. The aim is to induce a protective immune response without the risk of exposure to the real infection. Edward Jenner and Louis Pasteur discovered the principle of active immunisation with vaccines in the eighteenth and nineteenth centuries.
The term “vaccine” is derived from the Latin “vaccinus” meaning “from the cow”, because Jenner used mild infections with cowpox, which is not virulent for humans, but is sufficiently closely related to smallpox to induce a protective immune response. The widespread application of Jenner’s discovery ultimately led in the twentieth century to the eradication of smallpox from the world.
Another form of immunity is “passive” immunisation, where infection is treated by infusing antibodies derived from a person that has already made an immune response from active immunity into a person who needs one. Antibodies are proteins made during an immune response that recognise and inactivate an infectious organism. The first major application of Passive Immunity was the development of diphtheria antitoxin in the late nineteenth century.
One of the most attractive aspects of science is that we build on the foundations of our forebears. The cowpox virus (now known as “Vaccinia”) that Jenner used to prevent smallpox, has found a new application as an experimental vaccine for Ebola and other diseases. Advances in molecular biology have led to the development of versions of Vaccinia that can make parts of other infectious agents, and thus induce an active immunity to them. This works particularly well for the induction of protective antibodies.
Other viruses such as adenovirus, which causes “colds” in humans, can be modified in the same way. Two mild infectious vaccines can then be given sequentially that share only one component derived from a virulent organism such as Ebola. The result is an amplified active immune response to Ebola, without the risks involved with handling the Ebola virus itself.
Passive immunity with purified antibodies has resurfaced as a practical form of therapy. This followed the development of a method for isolating pure “monoclonal antibodies” from single clones of antibody producing cells by Kohler and Milstein in the 1970’s. This technology has been applied to the treatment of Ebola by infusing a mixture of antibodies that bind to different parts of the surface protein of the virus. In experimental settings this treatment can cure Ebola disease up to five days after the start of the infection.
The important point is that antibody treatment can be applied to any infectious agent. However, there is a subtle feature of antibodies that must be taken into account. Antibodies change during an immune response. There is a remarkable mechanism that introduces replacements in the amino acid building blocks of the antibody during an immune response. This change increases the strength with which the antibody binds to its target. In the trade this is called “affinity maturation”.
It seemed sensible to isolate antibodies to be used for therapy from humans that have recovered from a real infection, where we suspect that the antibodies will have “matured” sufficiently to be protective. On the other hand, careful work by Rolf Zinkernagel and colleagues had shown that immune responses to viruses don’t need much in the way of affinity maturation to provide protective antibodies. Obtaining samples from survivors can be difficult. It may involve risks from persistent virus or other pathogens, whereas healthy volunteers in vaccine trials are readily available.
We decided to find out if healthy volunteers receiving an experimental Ebola vaccine could provide a source of therapeutic antibodies. The vaccine was composed, as described above, of sequential shots of Adenovirus and Vaccinia virus modified to express the surface protein of Ebola. We isolated eighty-two antibodies from just eleven volunteers. We then identified groups of antibodies that bound independently to different regions of the Ebola surface protein.
Ultimately a mixture of four antibodies provided a curative treatment for guinea pigs with Ebola virus infection. The analysis of the amino acid sequences of the therapeutic antibodies revealed that some “affinity maturation” had taken place during the vaccine trial. However, it was less than that seen in the antibody response to influenza or HIV, where repeated or persistent exposures have taken place over a much longer period of time.
The management of an outbreak of Ebola, or other emerging infections, combines both types of intervention. Active immunisation with vaccines is used to prevent infections, and established infections are treated with therapeutic antibodies. We have shown that these two types of intervention can be developed together within the setting of an early phase clinical trial of an experimental vaccine. It is not necessary for the vaccine to be effective, as long as it induces even rare clones of therapeutic antibodies that can be identified by an efficient screening procedure.
Experimental vaccines for life-threatening infections, such as bird flu, SARS and MERS viruses are entering clinical trials. We strongly recommend that these trials be extended with a program of antibody isolation. This will add the value of an antibody therapy to the immunity induced by the vaccine: two golden benefits for the price of one.
The original paper can be found in Cell Reports.