Johnson & Johnson HIV Vaccine Candidate Fails Clinical Trials

Hope continues with research seeking for HIV vaccines with similar technology used against COVID-19

This year, the discovery of an incurable disease that has killed millions of people around the world completed 40 years: the Acquired Immunodeficiency Syndrome, better known by the acronym Aids. The number of deaths from it has fallen in recent years thanks to advances in scientific research, which is hard at seeking new treatments and prevention methods. However, since 1981, when the first case was diagnosed in the United States, 38 million people live with HIV worldwide, according to the World Health Organization (WHO). Despite the advances obtained in the knowledge of the pathogenesis, diagnosis and treatment of the disease, the development of effective vaccines and strategies capable of eradicating the virus are still unachieved goals. Social inequality is another factor that prevents solutions from reaching poor and vulnerable people.

The vaccine against HIV we dream of can help put an end to the disease epidemic, a goal outlined by the Joint United Nations Program on HIV/AIDS (UNAIDS) for 2030. But unfortunately it wasnt this time. The long-awaited vaccine developed by the Johnson & Johnson laboratory failed. During clinical trials, the vaccine candidate, despite not having caused serious side effects in the volunteers, also did not generate a satisfactory immune response. The effectiveness shown was only 25% in preventing infection. With this index, the researchers understood that it did not provide adequate protection in HIV prevention and the studies were closed. The researchers lamented the vaccines low efficacy, but emphasized that the data will be useful.

The clinical trial, which was named Imbokodo, began in 2017 and included more than 2 thousand women aged between 18 and 35 from five countries in sub-Saharan Africa (Malawi, Mozambique, South Africa, Zambia and Zimbabwe). The region was chosen for the study because vulnerable women and girls across the continent accounted for nearly two-thirds of new HIV infections in 2020. The results of the applications, completed on June 30, 2020, indicated that 63 of the 1.109 women in the placebo group had new HIV infections, while the proportion of infection among those vaccinated was 51 cases to 1.079 who received the experimental vaccine.

Infectologist and medical coordinator of clinical research at Hospital Emílio Ribas, Dr. Bernardo Porto Maia emphasizes that there is still no answer as to why, which resulted in an unsatisfactory result, at the first analysis of the Imbokodo clinical trial. “Every study is capable or not of reaching the objective it proposes. Several variables can interfere in this process, such as the key population for HIV infection in Africa; characteristics inherent to the specific subtype, predominant on that continent, as well as the very constitution of the immunizing agent, which uses the same platform (viral vector) as the investigational product used in the Mosaic study, but they present differences in the subtypes covered by the immunizing potential, he highlights . For him, these differences may have some relationship with possible different outcomes between the studies.

“Despite the unsatisfactory result, regarding the main objective of the Imbokodo study; the investigational product proved to be safe and sub-analyses will be carried out and, possibly, will contribute to the continuity of future research; in the same way as other studies, in the past, they served as a milestone for the improvement of techniques and technologies, which enabled the occurrence of studies, in different phases of clinical research, today, in the world, in the search for a global vaccine against HIV, adds Dr. Maia.

Dr. Rico Vasconcelos, an infectious disease physician and researcher at the University of São Paulo (USP), adds. “Although there were 25% fewer cases among vaccinated women, statistical analysis showed that this reduction in incidence cannot be attributed to the vaccine and is far below the minimum 50% incidence reduction expected by researchers. In other words, the results found in Imbokodo showed that there was no statistically significant difference in the incidence of HIV between cis-gender women who received the experimental vaccine and those who received placebo. Meaning women who received a placebo or the experimental vaccine had the same risk of becoming infected with HIV”, he says. For him, this happened for the same reason as the other dozens of vaccine attempts that have already been tested in clinical trials in the last 40 years of the epidemic: HIV has found ways to escape the immune response induced by the vaccine.

In a statement, the pharmaceutical ensured that HIV-infected participants during the study were referred to high-quality care and treatment services. Volunteers will also be informed if they received the vaccine or placebo. According to the scientific director of Johnson & Johnson, Dr. Paul Stoffels, the unique complexity of HIV and its ability to evade the human immune system remain challenges in developing vaccines against it. The same technology has been shown to be effective in the immunizations developed by J&J against Ebola and COVID-19. The technology applied in the Johnson & Johnson HIV vaccine candidate is the inactivated adenovirus, the same used in the AstraZeneca, Janssen and Sputnik V vaccines against COVID-19.

Vaccine in testing phase in Brazil

Despite the unsatisfactory results, the pharmaceutical giant is leading another parallel trial, called Mosaico. Dr. Bernardo Porto Maia, who is also the coordinator of the medical team for this study at Hospital Emílio Ribas, explains that Mosaico is a phase 3, multicenter and international clinical trial underway in eight countries on the American continent, including Brazil, and in Europe, where the virus strain differs from that prevalent in Africa. “The key population to HIV infection and therefore eligible for the study differs from that recruited in the Imbokodo study in Africa, which is men who have sex with other men and transgender people, with sexual vulnerability to sexually transmitted infection of HIV-1”, says Dr. Maia. Completion is scheduled for March 2024.

For Dr. Vasconcelos, who coordinates the same study, but at USP, the results of Imbokodo are worrying, but at the same time they do not harm the Mosaic. “Imbokodo was important, even though it didnt reach the desired result. It is these results that teach us more and more about immunization against HIV and give us the basis for the next steps in the search for an effective vaccine. Research, like life, is full of mistakes and successes. Mistakes teach us which path not to follow, and successes teach the correct paths to keep trying”, emphasizes the researcher. Regarding the difference between the two vaccines, Dr. Vasconcelos details that the vaccine used at Imbokodo has similar technology, which is the adenovirus 26 viral vector, however, despite being similar, they are different vaccines.

“In addition to the adenovirus applied in all 4 doses, the experimental vaccine tested in Africa added to the last two applications, a combination of gp140 proteins present in the viral envelope of HIV subtype C, the most prevalent in that continent. In the version of the vaccine used in Mosaico, the combination of gp140 proteins applied includes proteins from different HIV subtypes (A and B) and not just subtype C, which theoretically can improve protection”, concludes Dr. Vasconcelos. Preclinical trials of the Mosaico vaccine in monkeys found a 67% reduction in HIV incidence among vaccinated monkeys.

Differences between the two clinical studies

• Mosaico is performed in a different geographic region (Europe and the Americas) with a different HIV-1 predominant subtype (mainly Clade B).
• Mosaico is performed in a different study population (cis-gender men and trans individuals) with a different primary route of HIV-1 transmission (mostly intrarectal).
• The encouraging efficacy results demonstrated in preclinical animal studies used a Clade B virus, administered intrarectally as the “viral challenge”.
• Mosaic utilizes a different and improved vaccine regimen that includes the Mosaic gp140, protein, which has been shown to elicit a greater magnitude and broader humoral immune response, in addition to Ad26.Mos4.HIV and the clade C protein gp140.

Other vaccine candidates

Johnson & Johnson is not alone in the race to develop an HIV vaccine. Moderna is another one of them. The tests of two candidates are expected to start this month, but without a date to release the results. The vaccines developed use messenger RNA technology, the same used by the biotechnology company in its vaccine against COVID-19.

An article published in the New England Journal titled “Uhambo — Twists and Turns on the Journey to an Effective HIV-1 Vaccine”  cites studies of vaccines around the world. Among them, two are already closed: Thailand, carried out between 2003 and 2009, included men and women, and showed 31% effectiveness; South Africa, carried out between 2016 and 2020 with men and women, without proven effectiveness. In addition, the article makes reference to the study carried out in sub-Saharan Africa (HVTN 705), starting in 2017 and expected to end in 2022, which includes only women. Another study held in Europe, the United States and Latin America, starting in 2019 and ending in 2023, which includes men who have sex with men. And finally, sub-Saharan Africa (PrepVacc), starting in 2020 and ending in 2023, which includes men and women. Another study not mentioned in the article was successful in phase 1. In it, the International AIDS Vaccine Initiative (Iavi) and the Scripps Research Institute, in the United States, tested a new immunizing agent that stimulated the production of especially potent antibodies in 97% of the participants.

Scientists have made great strides in HIV treatment by turning what was once a death sentence into a manageable condition. Despite all the advances made, nearly two million new cases occur around the world each year, with more than 700 thousand deaths annually caused by AIDS, which shows that we have a long way to go in the definitive eradication of this scourge. The maintenance of combined prevention strategies, aimed at the most vulnerable populations, expansion of antiretroviral treatment, and persistence in the efforts to find a definitive solution (vaccine or cure) are still essential for us to turn this page in human history. And in this battle, equity in access to medicines is one of the most effective tools in eradicating infectious diseases.