SARS-coronavirus (SARS-CoV) was confirmed to be the etiological agent of severe acute respiratory syndrome (SARS), the first emerging human disease encountered in the 21st century . It is reported that SARS infection in humans is predominantly associated with mucosal transmission through lungs, intestine or even genital tract [20, 21, 26, 38, 40]. The appropriate anti-SARS-CoV antibody response, especially at diverse mucosal surfaces, would play a crucial role in protection against mucosal transmission of SARS-CoV. For example, the passive transfer of neutralizing serum antibody to naive mice prevented SARS-CoV replication in the lower respiratory tract following intranasal challenge . Prophylactic administration of the neutralizing human monoclonal antibody reduced replication of SARS-CoV in the lungs of infected ferrets, preventing the development of SARS-CoV induced macroscopic lung pathology . Besides, mucosal secretory IgA in the lower respiratory tract, immune protection in the digestive tract and other mucosal sites seems to be crucially important given the fact that transmission of SARS-CoV occurs by direct contact with droplets of the virus by the fecal or oral routes . Taken together, these reports suggest that a wide range of humoral immunity in systemic and diverse mucosal surfaces may play an important role in vaccine-induced protection against SARS-CoV transmission.
Mucosal immunity plays an important role in prevention of invasion by pathogens, which could be induced via systemic or mucosal immunization. However, both immunization protocols require an effective adjuvant to produce better immune responses. Mucosally delivered antigen in the absence of an adjuvant usually induces either a low or undetectable antigen-specific immune response or results in immune tolerance [7, 43]. At present, a few mucosal vaccines have been approved for human use in the United States or elsewhere. Examples include oral vaccines, which mostly comprise live attenuated antigens, against Poliovirus , V. cholerae, Salmonella typhi , and Rotavirus , and a nasal vaccine against influenza virus . It is becoming increasingly apparent that an effective mucosal adjuvant is a high priority in the development of efficient mucosal vaccine.
A synthetic dsRNA, termed Poly(I:C), has been found be able to boost immune responses since the 1960s [10, 45]. Recently, Poly(I:C) was discovered to function as an adjuvant through its interaction with TLR3, which in turn activates the NF-κB pathway, resulting in stable maturation of DCs, activation of NK cells and longer-time survival of activated CD4+ T cells in vitro . Ichinohe et al.  reported that intranasal vaccination of hemaglutinin (HA) adjuvanted with Poly(I:C) can induce protection against influenza viral infection in mice. Brian R. Sloat also showed that nasal immunization with anthrax PA plus Poly(I:C) can enhance the production of mucosal and systemic immunities . Therefore, Poly(I:C) represents another potential adjuvant. However, Poly(I:C) itself is unsuitable as a potential adjuvant because it is toxic and can be rapidly hydrolyzed in humans when used alone . Several Poly(I:C) derivatives have been suggested, such as Poly(ICLC), which is Poly(I:C) containing Poly-L-lysine and carboxymethylcellulose , to minimize observed deficiencies of Poly (I:C).
PIKA is a particular derivative of Poly(I:C) comprising kanamycin and calcium chloride . A phase I clinical trial with inactivated rabies vaccine in 20 healthy volunteers demonstrated that the PIKA adjuvanted rabies vaccine elicited an earlier detectable and higher neutralizing antibody titer. The PIKA adjuvanted vaccine was well tolerated. A study showed the parenteral adjuvant effect of PIKA in the induction of innate immune responses and HBsAg-specific IgG and IFN-γ responses in mice . Most recent studies also showed that PIKA can provide broad-spectrum prophylaxis against a number of influenza A viruses and coadministration of PIKA with a poorly immunogenic H5N1 subunit vaccine can lead to antigen sparing and quantitative and qualitative improvements of the immune responses over those achieved with an unadjuvanted vaccine in mice [18, 19]. In the present study, we demonstrated that the intraperitoneal and intranasal co-administration of this improved Poly (I:C) derivative induced strong anti-SARS-CoV mucosal and systemic humoral immune responses with neutralizing activity against pseudotyped virus.
PIKA Provides an Adjuvant Effect to Induce Strong Mucosal and Systemic Humoral Immunity Against SARS-CoV*
- Received Date: 17 January 2011
- Accepted Date: 18 February 2011
Abstract: Severe Acute Respiratory Syndrome (SARS) is a deadly infectious disease caused by SARS Coronavirus (SARS-CoV). Inactivated SARS-CoV has been explored as a vaccine against SARS-CoV. However, safe and potent adjuvants, especially with more efficient and economical needle-free vaccination are always needed more urgently in a pandemic. The development of a safe and effective mucosal adjuvant and vaccine for prevention of emergent infectious diseases such as SARS will be an important advancement. PIKA, a stabilized derivative of Poly (I:C), was previously reported to be safe and potent as adjuvant in mouse models. In the present study, we demonstrated that the intraperitoneal and intranasal co-administration of inactivated SARS-CoV vaccine together with this improved Poly (I:C) derivative induced strong anti-SARS-CoV mucosal and systemic humoral immune responses with neutralizing activity against pseudotyped virus. Although intraperitoneal immunization of inactivated SARS-CoV vaccine alone could induce a certain level of neutralizing activity in serum as well as in mucosal sites, co-administration of inactivated SARS-CoV vaccine with PIKA as adjuvant could induce a much higher neutralizing activity. When intranasal immunization was used, PIKA was obligatorily for inducing neutralizing activity in serum as well as in mucosal sites and was correlated with both mucosal IgA and mucosal IgG response. Overall, PIKA could be a good mucosal adjuvant candidate for inactivated SARS-CoV vaccine for use in possible future pandemic.