Pre-clinical follow-up study boosting with original formulation and next generation INO-4802 SARS-CoV-2 vaccine candidate

The rollout of different vaccines to reduce the risk of transmission and disease severity among patients with the coronavirus disease 2019 (COVID-19) has been historic. However, with every passing day over the past year after vaccine distribution began, there have been reports of reduced antibody titers among both convalescent and vaccinated individuals with multiple reports of breakthrough infections.

This indicates that the current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants have changed drastically from the original Wuhan-based strain, as they are often associated with enhanced transmissibility and the potential to evade immune responses.

Study: Prime-boost vaccination regimens with INO-4800 and INO-4802 augment and broaden immune responses against SARS-CoV-2 in nonhuman primates. Image Credit: Natali _ Mis /


Some of the notable SARS-CoV-2 variants of concern (VOC) include the Alpha (B.1.1.7), Beta (B.1.351), and Gamma (P.1) strains, as well as the currently predominant Delta (B.1.617.2) strain. An important question going forward is whether this immunity can be boosted by next-generation vaccines that target emerging variants while simultaneously maintaining long-term protection against existing strains.

Recent studies show that vaccine effectiveness of either the BNT162b2 or ChAdOx1 nCoV-19 vaccines is notably lower against the Delta (B.1.617.2) variant as compared to the Alpha (B.1.1.7) variant. The combination of viral escape mechanisms and waning immunity suggests that heterologous prime-boost strategies may be needed to provide sufficient coverage against novel variants.

Owing to the capacity of synthetic deoxyribonucleic acid (DNA) vaccines to initiate sufficient humoral and cell-based responses, along with added benefits of shortened clinical development, easy scale-up and manufacturing processes, and long-term temperature stability, researchers have studied such synthetic DNA vaccines and their effects in inducing longer, favorable immune responses in animal models, particularly primates.

In one recent study published on the preprint server bioRxiv*, researchers describe the antibody-inducing effects of DNA-based synthetic vaccines INO-4800 and INO-4802 and their benefits in prime-and-boost regimens against SARS-CoV-2 in non-human primates.

About the study

Previously, the researchers of the current study already had a reference of a synthetic DNA vaccine encoding the wild-type (Wuhan-Hu-1) spike protein. This vaccine, which was named INO-4800, has been shown to induce antigen-specific T-cell responses and functional antibodies that neutralize SARS-CoV-2 in preclinical studies.

In a non-human primate (NHP) challenge model, INO-4800 vaccination was associated with reduced viral loads and protection against respiratory tract disease. Phase I and II clinical trials of INO-4800 demonstrated favorable safety and tolerability profiles and immunogenicity.

In an effort to devise an even more effective vaccine, the researchers have designed INO-4802, which is a next-generation DNA vaccine expressing a pan-spike immunogen that has been shown to raise immunity across SARS-CoV-2 VOCs in animal models.

In this study, researchers investigated the durability and memory recall of antigen-specific SARS CoV-2 responses in a cohort of NHPs that were initially primed with the first-generation SARS-CoV-2 vaccine INO-4800.

Rhesus macaques were primed over one year prior with the first-generation INO-4800 vaccine. They were boosted with either INO-4800 or INO-4802 in homologous or heterologous prime-boost regimens.

Both boosting schedules led to an expansion of antibody responses that were characterized by improved neutralizing and angiotensin-converting enzyme 2 (ACE2) blocking activity across wild-type SARS-CoV-2, as well as multiple VOCs. However, the most notable observation was that the heterologous booster doses of the next-generation INO-4802 were able to induce even higher cell-mediated and humoral immune responses as compared to homologous booster with INO-4800.


The current study addresses two major concerns over vaccine rollouts globally, including the global shortage of vaccines and the ability of VOCs to escape immune responses from the available set of messenger ribonucleic acid (mRNA)- and vector-based vaccines.

Synthetic DNA-based vaccines are easier to manufacture, scale-up, and store. Additionally, heterologous boosters with these vaccines can also combat the most concerning VOCs like the Delta VOC.

These data illustrate the durability of immunity following vaccination with INO-4800 and support the use of either INO-4800 or INO-4802 in prime-boost regimens. Since NHPs have responded well to these trials, the findings of the current study support the transition to human trials with these vaccines in the near future.

*Important notice

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:

Gemma Wilson

Gemma is a journalism graduate with keen interest in covering business news – specifically startups. She has as a keen eye for technologies and has predicted quite a few successful startups over the last couple of years.

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