Two-step HIV vaccine approach sparks hope for better protection

Through centuries of disease outbreaks, vaccines have been an essential public health tool. Human immunodeficiency virus (HIV), however, has proved stubbornly resistant to vaccination efforts. One barrier facing HIV vaccine developers is that B cells must produce a substantial and broad antibody response to neutralize HIV’s mutation-prone genome effectively. Many antibody binding sites on the virus’s surface are non-neutralizing; targeting these sites does not affect the virus’s spread. Many vaccines produce ineffective immune responses.

In 2019, researchers at the Massachusetts Institute of Technology (MIT) developed a new dosing strategy that pumped up antibody output, increasing the chances that a substantial number of neutralizing antibodies would be produced (1). Instead of a single injection, called a bolus, the researchers administered the vaccine in seven escalating doses over two weeks. This schedule produced antibody levels that were 20 times higher than bolus injection.

But this discovery, which was exciting in theory, led to a dead end in practice. Public vaccination campaigns are already fraught with difficulty, and the team found that the ideal escalating dose regimen involved no fewer than seven injections.

Now, a research team has identified a dosing approach that, at least in mice, produces a massive immune response with a greatly shortened dosing schedule, recently published in Science Immunology (2).

“We could do just about as good as the more complex dosing regimen,” said Darrell Irvine, one of the senior authors of the new study, a coauthor on the 2019 paper, and an immunologist at Scripps Research.

We could do just about as good as the more complex dosing regimen.
- Darrell Irvine, Scripps Research

The vaccine itself used a protein from HIV’s protein envelope combined with an adjuvant called saponin/monophosphoryl lipid A (MPLA) nanoparticles (SMNP). In mouse studies, the team administered this vaccine as a bolus or split it into two, three, four, five, six, or seven doses. The two-dose regimen initially produced a weak immune response compared to the other multipart approaches. In further testing, the team found that a modified schedule — comprising a smaller first dose of 20 percent of the vaccine, with the remaining 80 percent seven days later — produced a powerful swell of antibodies in line with the more complex dosing regimens.

The team then interrogated the mice’s reactions to these varied regimes. In experiments led by Irvine’s coauthor Arup Chakraborty, a chemical engineer at MIT, the team simulated the immune response to vaccination in silico.

These analyses revealed why the multistep approach effectively ramped up immune responses. A key event in a successful immune response to vaccination is when vaccine antigens reach areas of the lymph nodes called germinal centers — where B cells become activated and pump out antibodies. The analysis showed that after a single vaccine dose, very little of the vaccine antigen reached the germinal centers, producing few antibodies.

In the two-step regimen, the small initial immunization also produced few antibodies. But these hung around in the body until the second, larger dose arrived a week later. The antibodies quickly formed immune complexes with the antigens in the second dose. These complexes are better able to access germinal centers and stimulate long-lasting B cell antibody production.

The two-step approach yielded an antibody response 10 times greater than a bolus injection.

Mice, however, have a different repertoire of antibodies than humans, Irvine said. This means the team can’t assess how well the approach protects against disease without further study in non-human primates, which is already ongoing. Tomáš Hanke, an immunologist at the University of Oxford who wasn’t involved in the study, said the work was “promising” but both he and Irvine added that more work will be required to produce an effective vaccine.