South America Attenuates the Neutralizing Antibody Response to Yellow Fever Immunization

NEW YORK (Reuters Health) – The yellow fever virus (YFV) vaccine may not do as well at neutralizing the current Brazilian strain as it does against the virulent strain in Africa, challenging the World Health Organization’s global strategy to eliminate YF epidemics, researchers say.

“There are genetic differences between YFVs circulating in Africa versus South America that reduce the potency of the neutralizing antibody response against South American YFV strains,” Dr. Kartik Chandran and Dr. Denise Haslwanter, both of Albert Einstein College of Medicine in New York City told Reuters Health.

“Currently, antibody neutralizing activity in blood taken from vaccinees is used as a surrogate of protection, although this is likely an imperfect measure,” they said by email. “However, this measurement is done using an African virus and not a South American virus. The strain mismatch could lead to an overestimate of how the antibodies elicited by vaccination will perform against the South American viral strains that these individuals may be exposed to.”

“We believe public health laboratories in South America should re-evaluate how this measurement is done,” they added. “Our work shows that using a South American viral strain should provide a more realistic assessment of the vaccine-elicited antibody response.”

As Drs. Chandran and Haslwanter noted, the induction of neutralizing, or viral entry-blocking, antibodies targeting the envelope protein, E, is considered the most important surrogate marker for vaccine-induced protection, and may be the major mechanism that confers long-lasting protection against flavivirus disease.

The team shows in Cell Host and Microbe that the neutralization potency of the YFV vaccine-induced human polyclonal antibody and monoclonal antibody responses against the endemic Brazilian YFV 2017-19 strain is substantially lower than predicted from classical potency assays using the vaccine strains or a wild-type African YFV strain.

Analyses of antibody responses from vaccinated donors showed the reduction was largely attributable to genetic changes at two sites in the central domain II of the YFV 2017-19 E protein.

A phylogenetic analysis of YFV genome sequences showed that these changes were not present in African and Asian (ex-African) sequences; however, they are shared among essentially all South American sequences dating back to 1977.

Analyses of the neutralizing antibody response to the South American vaccine showed blunted neutralization activity soon after vaccination and “substantially reduced” neutralization potency relative to the vaccine strain at later times in three of five donors.

Analyses of donor sera from larger groups of US and Brazilian vaccinees corroborated the trend, revealing significant reductions in vaccine strain neutralization.

Drs. Chandran and Haslwanter said, “We are not saying that the vaccine is less effective in South America than in Africa–there is no evidence for this and we didn’t look at vaccine effectiveness in our study. It is entirely possible that the existing, though lower, neutralizing activity may be enough to block viral infection. Further, other arms of the immune response, such as effector T cells, may not be impaired.”

“This parallels the ongoing discussion about the relationship between antibody neutralizing activity and vaccine effectiveness against SARS-CoV-2 and its variants,” they note. “As with COVID-19, we also need to make a distinction between breakthrough infections and disease. The reduction in neutralizing antibodies may affect the former but not the latter–we simply don’t know.”

Dr. Mark Heise, a Professor of Genetics, Microbiology and Immunology at the University of North Carolina told Reuters Health by email, “The study has important implications for YFV vaccination efforts. It illustrates the importance of using antigenically appropriate indicator viruses when measuring YFV vaccine performance in South American countries.”

“Additional studies are needed to assess other aspects of vaccine-induced immunity, including effects of the viral mutations on T cell epitopes,” he said. “Furthermore, studies need to be conducted to assess rates of vaccine breakthrough resulting in clinical disease in South America.”

“The simplest strategy for updating the vaccine is likely to involve introducing the mutations identified by the authors into the 17-D vaccine strain, although this would likely require extensive safety and efficacy testing,” he said. “Alternatively, include the South African YFV- derived antigen in other vaccine platforms, such as mRNA vaccines. However, I think this would likely be premature until results are in from efficacy studies.”

Meanwhile, he added, “Clinicians should be on the lookout for breakthrough infections occurring in vaccinated persons living or traveling in South America.”

SOURCE: https://bit.ly/3eZmNsG Cell Host and Microbe, online January 7, 2022.