Low seroprevalence of neutralizing antibodies to gorilla adenovirus 32 (GRAd32) in southern African populations supports evaluation of this vector platform for HIV vaccine development

This study demonstrates that southern African populations exhibit low pre-existing seroprevalence of neutralizing antibodies against gorilla adenovirus 32 (GRAd32), which remains unaffected by Ad26-based COVID-19 vaccination, thereby supporting its potential as an effective vector platform for future HIV vaccine trials in the region.

The Gist

Imagine your immune system is a highly trained security team at a busy airport. Its job is to spot and stop "bad guys" (viruses) trying to get in. But sometimes, this security team gets confused by "good guys" that look too much like the bad guys.

In the world of vaccines, scientists use harmless viruses called adenoviruses as delivery trucks to carry vaccine instructions into your body. The most common delivery truck used in the past has been Ad5. However, because so many people have already been exposed to Ad5 in their lives, their security teams have already memorized its face. When a new vaccine arrives in an Ad5 truck, the security team attacks the truck itself before it can even deliver the message. This is like a guard stopping a delivery driver because they recognize the uniform, not realizing the driver is actually there to help.

To solve this, scientists invented a new type of delivery truck: GRAd32. This truck is based on a gorilla adenovirus, a species that humans rarely encounter. The hope is that our security teams haven't seen this truck before, so they won't stop it, allowing the vaccine message to get through.

The Big Question
The researchers wanted to know: In Southern Africa (specifically South Africa and Zimbabwe), how many people already have security guards trained to recognize this new gorilla truck (GRAd32)? They also wanted to see if the recent global rush of COVID-19 vaccines had accidentally trained these security guards to recognize the gorilla truck by mistake.

The Investigation
The team took blood samples from two groups of people:

1. South Africans: Some were about to get a specific COVID-19 vaccine (Ad26.COV2.S), and others were getting a booster shot later.
2. Zimbabweans: Some had never been vaccinated, while others had received inactivated COVID-19 vaccines (like Sinopharm or Sinovac).

They checked these samples for "neutralizing antibodies," which are essentially the security guards' "wanted posters." If you have a high number of posters for a specific virus, your body is ready to fight it immediately.

What They Found

• The Old Truck (Ad5): Almost everyone (about 68% to 69%) already had a "wanted poster" for the old Ad5 truck. Their security teams were very familiar with it.
• The Middle Truck (Ad26): A good chunk of people (32% to 42%) had seen this one before.
• The New Gorilla Truck (GRAd32): Very few people (only 14% to 22%) had ever seen this truck. Their security teams were mostly clueless about it. This is great news because it means the truck can likely slip past the guards and deliver its message.

The COVID-19 Twist
The researchers also checked if getting COVID-19 vaccines changed the situation:

• Inactivated Vaccines: Getting shots like Sinopharm or Sinovac didn't change the guards' knowledge of any of the trucks.
• The Ad26 Vaccine: When people got the Ad26-based COVID-19 vaccine, their security teams learned to recognize the Ad26 truck very quickly (the "wanted posters" went up 10-fold). However, this training did not accidentally teach them to recognize the gorilla truck (GRAd32). The guards remained clueless about the gorilla truck, even after being trained on the Ad26 truck.

HIV Status
The study also looked at people living with HIV versus those without. They found that HIV status didn't change the results; the security teams of both groups reacted the same way to these trucks.

The Conclusion
The study confirms that the gorilla truck (GRAd32) is a rare sight in Southern Africa. Most people's immune systems haven't seen it, and getting other common vaccines (even the Ad26-based ones) doesn't make them suddenly recognize it. This suggests that the GRAd32 truck is a safe and effective choice for delivering future HIV vaccines in this region, as it is unlikely to be blocked by pre-existing immunity.

Technical Summary

Technical Summary: Seroprevalence of GRAd32 in Southern Africa and Implications for HIV Vaccine Development

Problem Statement
Adenovirus (Ad) vectors are a cornerstone of vaccine development; however, their efficacy is often compromised by pre-existing immunity to common serotypes, particularly Ad5. Neutralizing antibody (nAb) titers exceeding 200 have been demonstrated to significantly diminish vaccine immunogenicity. While Gorilla adenovirus (GRAd) vectors, such as GRAd32, were engineered to evade these pre-existing anti-vector responses, their seroprevalence in southern African populations remains poorly characterized. This lack of data creates uncertainty regarding the suitability of GRAd32 for HIV vaccine trials in regions where Ad5 and Ad26 vectors are already widespread, and where Ad26-based COVID-19 vaccines have been extensively deployed.

Methodology
The study assessed the seroprevalence of neutralizing antibodies against GRAd32, Ad26, and Ad5 in cohorts from South Africa and Zimbabwe. The investigation utilized a multi-cohort approach:

• South African Cohorts: Sera were collected from the Sisonke sub-study (n=100, pre-Ad26.COV2.S vaccination) and the Booster after Sisonke (BaSiS) study (n=226). This included paired pre- and post-boost samples for 27 donors.
• Zimbabwean Cohort: Sera were obtained from the Mutala cohort (n=131), comprising 44 unvaccinated individuals and 87 individuals vaccinated with inactivated vaccines (Sinopharm/Sinovac).
• Demographics: Participants living with HIV (PLWH) constituted 30–50% of each cohort, allowing for stratification by HIV status.
• Assessment: Neutralizing antibody titers were measured at baseline and, where applicable, after COVID-19 vaccination. The study specifically analyzed the impact of Ad26.COV2.S vaccination on GRAd32 titers using longitudinal samples.

Key Results

• Baseline Seroprevalence: In the pre-vaccination Sisonke cohort, geometric mean titers (GMT) for GRAd32, Ad26, and Ad5 were 78, 142, and 459, respectively. The proportion of participants with neutralizing titers >200 was 14% for GRAd32, 32% for Ad26, and 68% for Ad5. Similar trends were observed in the unvaccinated Mutala cohort (GMTs: 117, 245, 536; prevalence >200: 22%, 42%, 69%).
• HIV Status: No significant differences in antibody titers were observed between PLWH and HIV-negative individuals across the measured vectors.
• Impact of COVID-19 Vaccination:
  • Inactivated Vaccines: Vaccination with Sinopharm/Sinovac did not significantly alter titers for Ad5, Ad26, or GRAd32.
  • Ad26.COV2.S Vaccination: Longitudinal analysis of 27 donors revealed a 10-fold increase in anti-Ad26 titers (GMT rising from 141 to 1,426) approximately 9 months post-vaccination. In contrast, anti-GRAd32 responses remained statistically unchanged, and anti-Ad5 responses showed only a modest (<2-fold) increase.

Significance and Claims
The paper concludes that while anti-Ad5 neutralizing antibody responses are ubiquitous globally, GRAd32 responses are significantly less frequent in southern African populations. Crucially, the study demonstrates that GRAd32 neutralizing responses are not cross-boosted or significantly altered by Ad26.COV2.S vaccination.

The authors assert that these findings support the continued evaluation of the GRAd32 vector platform for HIV vaccine development. Specifically, the data suggest that GRAd32 remains a viable candidate for upcoming HIV vaccine trials, even in regions where Ad26-based COVID-19 vaccines have been widely deployed, as the pre-existing immunity to Ad26 does not appear to compromise the utility of the GRAd32 vector.