Johnson & Johnson's Ad26.COV2.S COVID-19 Vaccine Candidate Demonstrates Robust Antibody and T Cell Immune Responses After a Single Dose in Phase 1/2a Trial

Recently, Johnson & Johnson announced the launch of ENSEMBLE, a large-scale, pivotal Phase 3 clinical trial, which plans to enroll 60,000 volunteers to evaluate the safety and efficacy of its candidate COVID-19 vaccine, JNJ-78436735 (also known as Ad26.COV2.S), in preventing COVID-19 disease. The company released the safety and immunogenicity results from its Phase 1/2a clinical trial of this candidate vaccine on the preprint server medRxiv. Interim trial results showed that a single dose of the candidate vaccine elicited robust antibody and T-cell immune responses in both adult and elderly populations.

Ad26.COV2.S is a candidate COVID-19 vaccine developed by Janssen, a subsidiary of Johnson & Johnson, based on a non-replicating adenovirus vector. It utilizes the serotype 26 adenovirus vector (Ad26) to express the prefusion SARS-CoV-2 spike protein (S protein). In this clinical trial, adult participants aged 18–55 years were divided into two groups (Cohorts 1a and 1b) to receive either one or two doses of the Ad26.COV2.S vaccine, or placebo. The trial also included a cohort of healthy older adults aged 65 years and above (Cohort 3). The study published in medRxiv reported safety data for Cohorts 1a, 1b, and 3, as well as immunogenicity data for Cohorts 1a and 3.

Safety Data

Ad26.COV2.S demonstrated favorable safety and tolerability, with the most common adverse event (AE) being injection-site pain. In the adult cohort aged 18–55 years (Cohort 1a), 64% of participants reported systemic adverse events, with the most common reactions being fatigue, headache, and myalgia. Fever occurred in 19% of participants; however, all fever events emerged within 2 days post-vaccination and resolved within 1–2 days.

Notably, in the elderly cohort aged over 65 years, only 36% of participants reported systemic adverse events. This finding suggests that this candidate vaccine may elicit fewer systemic adverse events in older adults than in younger adults.

▲Safety Data for Ad26.COV2.S (Image Source: Reference [1])

Antibody-Mediated Immune Response

In this trial, participants received vaccination with a dose of 5E10 (low dose) or 1E11 (high dose) viral particles (vp). Among participants in Cohort 1a, 99% seroconverted from negative to positive for antibodies against the SARS-CoV-2 spike (S) protein 29 days after a single vaccine dose. In the elderly subgroup aged over 65 years, 100% of participants showed a significant increase in antibody levels against the S protein.

Using the wild-type virus neutralization assay (wtVNA), researchers found that 29 days after a single dose of the candidate vaccine, 92% of participants in the adult group and 11 out of 12 participants in the elderly group exhibited seroconversion of neutralizing antibodies. The researchers noted that among participants in Cohort 1a, 82% of those who received the low-dose candidate vaccine and 94% of those who received the high-dose candidate vaccine had neutralizing antibody titers exceeding 100, indicating that a single dose of Ad26.COV2.S can elicit a robust antibody immune response in most participants.

▲Ad26.COV2.S elicits antibody responses against the S protein (A) and neutralizing antibody responses (B) (Image source: Reference [1])

Cell-mediated immune response

Researchers have pointed out that preclinical studies of SARS-CoV and MERS-CoV vaccines have shown that a Th2-biased CD4+ T cell response may be associated with vaccine-associated enhanced respiratory disease (VAERD). Therefore, researchers examined the type of CD4+ T cell response elicited by Ad26.COV2.S.

The trial results showed that in both the adult and elderly participant groups, the majority of participants developed detectable Th1-type CD4+ T cell responses, with only one participant in the adult group exhibiting a detectable Th2-type CD4+ T cell response. In this participant, the Th1/Th2 response ratio was 28.9, indicating a Th1 bias in the CD4+ T cell response.

▲Ad26.COV2.S-induced CD4+ T cell response (Image source: Reference [1])

Meanwhile, researchers also found that S protein-specific CD8+ T cell responses were detected in both the adult and elderly groups 15 days after a single vaccine dose. In the discussion section of the article, the researchers pointed out that a robust CD4+ Th1 immune response, combined with CD8+ T cell responses and antibody responses, would minimize the theoretical risk of vaccine-associated enhanced respiratory disease.

Some Discussions

During the discussion session, researchers pointed out that current data are insufficient to determine the durability of the immune response elicited by the Ad26.COV2.S candidate vaccine. In previous studies of Zika virus vaccines developed using the same vector platform, a single dose maintained neutralizing antibody seropositivity in 56% of recipients for at least 12 months.

However, the durability of immunity depends not only on the maintenance of neutralizing antibody levels but also on the extent to which the vaccine elicits immune memory. Immune memory refers to the process whereby the immune response generated by the vaccine leads to the persistence of memory B cells and memory T cells, capable of recognizing SARS-CoV-2-specific antigens, in the bone marrow. Upon re-exposure to the virus, these cells enable a more rapid production of neutralizing antibodies and T-cell responses. In this regard, researchers will use very low doses of the candidate viral vaccine in Phase 2a clinical trials to simulate SARS-CoV-2 infection and assess the immune memory responses in vaccinated participants.

Given that the immunogenicity responses elicited by the low-dose and high-dose candidate vaccines were comparable, researchers will use the low dose of 5E10 vp for further studies in subsequent trials.

References:

[1] Sadoff, et al., (2020). Safety and immunogenicity of the Ad26.COV2.S COVID-19 vaccine candidate: interim results of a phase 1/2a, double-blind, randomized, placebo-controlled trial. medRxiv, https://doi.org/10.1101/2020.09.23.20199604

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