Heterologous prime-boost: breaking the protective immune response bottleneck of COVID-19 vaccine candidates

Emerg Microbes Infect. 2021 Dec;10(1):629-637. doi: 10.1080/22221751.2021.1902245.


COVID-19 vaccines emerging from different platforms differ in efficacy, duration of protection, and side effects. To maximize the benefits of vaccination, we explored the utility of employing a heterologous prime-boost strategy in which different combinations of the four types of leading COVID-19 vaccine candidates that are undergoing clinical trials in China were tested in a mouse model. Our results showed that sequential immunization with adenovirus vectored vaccine followed by inactivated/recombinant subunit/mRNA vaccine administration specifically increased levels of neutralizing antibodies and promoted the modulation of antibody responses to predominantly neutralizing antibodies. Moreover, a heterologous prime-boost regimen with an adenovirus vector vaccine also improved Th1-biased T cell responses. Our results provide new ideas for the development and application of COVID-19 vaccines to control the SARS-CoV-2 pandemic.

Keywords: COVID-19 vaccine; Heterologous prime-boost; T cell response; neutralizing antibody; th1/th2 balance.

MeSH terms

  • Adenovirus Vaccines / administration & dosage
  • Adenovirus Vaccines / immunology*
  • Animals
  • Antibodies, Neutralizing / blood
  • Antibodies, Neutralizing / immunology
  • Antibodies, Viral / blood*
  • Antibodies, Viral / immunology
  • COVID-19 / prevention & control
  • COVID-19 Vaccines / adverse effects
  • COVID-19 Vaccines / immunology*
  • Immunization, Secondary / methods*
  • Interferon-gamma / blood
  • Lymphocyte Count
  • Mice
  • Mice, Inbred BALB C
  • SARS-CoV-2 / immunology
  • T-Lymphocytes / immunology
  • T-Lymphocytes, Helper-Inducer / immunology
  • Vaccination / adverse effects
  • Vaccines, Subunit / administration & dosage
  • Vaccines, Subunit / immunology*
  • Vaccines, Synthetic / administration & dosage
  • Vaccines, Synthetic / immunology*


  • Adenovirus Vaccines
  • Antibodies, Neutralizing
  • Antibodies, Viral
  • COVID-19 Vaccines
  • IFNG protein, mouse
  • Vaccines, Subunit
  • Vaccines, Synthetic
  • mRNA Vaccine
  • Interferon-gamma

Grant support

This work was supported by Major Special Projects Funding Program of the Ministry of Science and Technology of the People’s Republic of China. [grant number 2020YFC0860500].